3613 results for "*geneti*"

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• Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

  Study phs004080

• Imaging Genetics of Spasmodic Dysphonia

  Laryngeal dystonia (LD), or spasmodic dysphonia, is isolated focal dystonia characterized by selective impairment of speech production due to involuntary spasms in the laryngeal muscles. Despite well-characterized clinical features of LD, its clinical management remains challenging due, in part, to the absence of objective measures (biomarkers) for early detection and differential diagnosis. This results in diagnostic inaccuracies, which have a negative impact on the patient's quality of life and healthcare costs. Importantly, delayed diagnosis leads to deferred treatment. The objective of this application is to conduct a series of studies that combine advanced machine-learning with neuroimaging and genetics to (1) identify the neural markers that accurately differentiate LD between its clinical phenotypes (adductor vs. abductor), genotypes (sporadic vs. familial), and comorbid disorders (voice tremor and muscle tension dysphonia); (2) determine the early predictive neural markers of LD development in at-risk individuals, and (3) validate associated LD gene mutations. Supported by our preliminary data, our central hypothesis is that brain abnormalities are shaped, in part, by underlying genetic factors and exhibit LD form-characteristic features, which can be used as differential diagnostic and early predictive biomarkers of this disorder. Data submitted to dbGaP consist of sequences and phenotype information.

  Study phs004887

• Elucidation of Genotype-Phenotype Relationships Using Human Stem Cell Models

  Our goal of this work is to determine how natural human genetic variation influences molecular and cellular phenotypes using human pluripotent stem cell (hPSC) cells and their derivatives. This project utilizes the “cell village” approach in which hPSCs (or their derivatives) from many different genetically-distinct donors are pooled together in shared in vitro environments for high throughput multi-modal phenotyping. Genotypes for each donor are collected prior to village construction using whole genome sequencing or SNP array profiling followed by whole genome imputation. Molecular phenotypes for each donor are ascertained via single-cell RNA sequencing followed by Dropulation-based donor de-multiplexing. Finally, cellular phenotypes are quantified using low coverage (0.5-1X) whole genome sequencing of the village followed by Census-seq computation of donor proportions. By capturing genetic, molecular, and cellular phenotyping heterogeneity in a uniform environment, we can detect relationships among alleles, molecules, and cellular traits. The project data registered with the study includes assessments of cell fitness, defined as a cell's ability to proliferate and survive: (1) Low coverage (0.5X-1x) whole genome sequencing data from a human embryonic stem cell (hESC)-derived neural progenitor cell village consisting of 38 donors that was harvested at multiple time points (Day 0, 1, 5, 6, and 10) to quantify differential baseline growth rates among donors.(2) Low coverage (0.5X-1x) whole genome sequencing data from a human embryonic stem cell (hESC)-derived neural progenitor cell village consisting of 38 donors that was harvested at multiple time points (Day 0, 4, and 7) after exposure to a vehicle control, 3 uM, or 10 uM lead (Pb) acetate to quantify differential Pb sensitivities across donors. (3) Low coverage (0.5X-1x) whole genome sequencing data from a human induced pluripotent stem cell (hiPSC)-derived neural progenitor cell village composed of eleven neurotypical controls and twelve 16p11.2 deletion patients harvested at multiple time points (Day 0, 1, 5, 6, 10) to quantify case-control differences in baseline growth rates.

  Study phs004608

• Lineage Heterogeneity and Plasticity in Lung Cancer

  Our previous studies found lung cancer cells harboring amplification of lineage oncogenes are specifically dependent on their expression for survival. The need for lineage amplified genes in a subset of cancers suggests unique vulnerabilities in cancer cells that may be poised on the brink of survival. However, these amplifications represent only a minor subset of the two major subtypes of lung cancers. Therefore, this study focuses on the lineage factors that are essential during the development and control cell identity in adult cells, in the remaining subsets of lung cancers. Through genome-wide profiling of a histone marks, we identified ‘super-enhancers' (SE) on lineage-defining transcription factor genes. Subsequent hierarchical clustering of lung cancer samples identified SEs specific to subsets of lung cancers. We aim to understand the significance of factors defining the lineage state of the newly defined subsets of lung cancers.

  Study phs004458

• Field Studies of Human Immunity to Amebiasis in Bangladesh

  Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission.

  Study phs001476

• CIDR/NICHD Genetic Basis of Recessive Pediatric Brain Diseases

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including cerebellar hypoplasia (CBH), lissencephaly (LIS), microcephaly (MIC), corpus callosum hypoplasia (CCH), pontocerebellar hypoplasia (PCH), pontine tegmental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001060

• HIV Associated Reservoirs and Comorbidities Study (HARC)

  Despite effective antiretroviral therapy (ART), people with HIV (PWH) are at risk for central nervous system (CNS) abnormalities, including cognitive impairment. B cells and antibodies are key mediators of adaptive immunity in neuroinflammatory disorders and crucial for viral control, but their role in HIV-associated CNS pathology is unknown. Here, we apply multimodal transcriptomic, epigenetic, and B-cell receptor profiling of B cells across cerebrospinal fluid (CSF), choroid plexus, and blood from ART-treated PWH and people without HIV, alongside neurocognitive assessments. In ART-suppressed PWH, CSF resting memory B cells exhibit impaired pathogen responsiveness, and high antibody gene mutations, suggesting CNS-restricted antigenic adaptation. Choroid plexus B cells exhibit similar transcriptomic immune perturbations despite viral suppression. Notably, CNS-specific B-cell molecular alterations are associated with poorer neurocognitive performance. These findings suggest that, despite long-term ART suppression, CNS memory B cells show suppressed antiviral pathways but increased antigen experience and trafficking, indicating dysregulated CNS immune surveillance and positioning them as key contributors to HIV-associated neuroimmune dysfunction.

  Study phs004745

• Defining Intrinsic and Acquired Mechanisms of Immune Checkpoint Blockade Resistance in Glioblastoma

  To systematically investigate the genomic features associated with benefit from anti-PD(L)1 in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM), we profiled 181 GBM cases (43 newly diagnosed, 138 recurrent) by whole exome sequencing (WES), targeted panel sequencing, and bulk RNA-sequencing (RNA-Seq). In multivariate survival analysis, baseline tumor transcriptional subtype and presence of their associated genetic lesions emerged as key features predicting overall survival (OS) among newly-diagnosed GBM treated with anti-PD(L)1, with the mesenchymal (MES) subtype associated with improved OS and the proneural subtype associated with poorer OS. Exposure to immune checkpoint blockade (ICB) was associated with outgrowth of subclones harboring lesions associated with non-MES subtype (CDKN2A deletions, PDGFRA gain-of-function mutations), which was not observed in analogous analyses of an external ICB-naive cohort. Our studies support the notion of an MES to non-MES transition as a common trajectory following ICB treatment for GBM.

  Study phs003614

• Circulating, Cell-Free DNA Methylation Patterns Indicate Cellular Sources of Allograft Injury after Liver Transplant

  Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed longitudinal blood samples collected from patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damage post-transplant recovers in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.

  Study phs003610

• CIDR-Whole Genome Sequencing: Prospective Birth Cohort to Elucidate Etiology of ADHD in US Minority Children

  Attention Deficit Hyperactivity Disorder (ADHD) is the most common pediatric developmental disability, affecting at least 6 million U.S. children; children from minority racial and ethnic populations, such as Black children, are at even higher risk. A major challenge in preventing and treating ADHD is that the causes remain unclear. Available data suggest that both genetic and early life environmental factors may play a role. On the genetics forefront, although an increasing number of genome-wide association studies (GWAS) have been conducted, and many genetic variants have been linked to risk of ADHD, these loci only explain a small fraction of ADHD. One puzzle has been the substantial discrepancy in estimated heritability of ADHD by GWAS (10% to 28%) vs. family-based studies (~80%). This so called “missing heritability” could be due to limitations of available arrays for conducting GWAS. For example, loci identified by GWAS could simply be surrogates for causal variants and/or functional genes associated with ADHD, and important single nucleotide variations (SNVs) or genetic structural variants (SVs) are not captured by GWAS. To advance the field, we integrated whole genome sequencing (WGS) with a well-established and well-phenotyped prospective Boston Birth Cohort (BBC) comprised of predominantly US, Black children from under-resourced urban settings. These children were enrolled at birth and followed up to age 21 years. We performed WGS for 500 Black children, about half with clinically diagnosed ADHD and another half neurotypical children. WGS offers an unprecedented opportunity to examine the entire genome, including rare SNVs (including insertion or deletions), SNVs in the noncoding region (a potentially large and hitherto unexplored class of variations), and SVs (including copy number variations) not captured by current arrays for GWAS. We anticipate that this study will enable us to gain deeper insight into the genetic architecture underlying the development of ADHD, its findings will be directly relevant to reduce the health disparity of ADHD in the United States.

  Study phs003431

• Long-Term Isolation and Archaic Introgression Shape Functional Genetic Variation in Near Oceania

  We generated 175 whole-genome sequences (WGS) from 12 populations across the Bismarck Archipelago and Bougainville (Papua New Guinea). We used these data to infer the evolutionary history of these populations, quantify levels of Neandertal and Denisovan ancestry, detect signatures of positive selection, and functionally characterize genetic variants introgressed from Neandertals and Denisovans. FASTQ files for 175 individuals and variant calls jointly genotyped with a larger dataset of worldwide humans are made available. These genotype calls include samples from the Human Genome Diversity Project (HGDP, PRJEB6463), HGDP samples sequenced by the Simons Genome Diversity Project (SGDP, PRJEB9586), as well as samples from Vernot et al. 2016 (phs001085.v1.p1) and Tucci et al. 2018 (phs001633.v1.p1).

  Study phs004464

• Childhood Cancer Data Initiative (CCDI): Texas Pediatric Patient Derived Xenograft 

  The DNA/RNA samples of patients for which PDX models were developed were from a population of children, adolescents, and young adults from South Texas. Consent was obtained for collection of malignant and non-malignant tissue samples for genetic analysis and for the development of models to study new ways to treat cancer. For additional details, please refer to these publications: PMID: 37915590; PMID: 37990009.

  Study phs003215

• Lipid Research Clinics - Prevalence Study (LRC-PS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Veterans Administration (VA) Million Veteran Program (MVP) Summary Results from Omics Studies

  MVP is an ongoing prospective cohort study and mega-biobank in the Department of Veterans Affairs Healthcare System designed to study genetic influences on health and disease among veterans.

  Study phs001672

• KOLF2.1J iPSC and Differentiated Cell Types

  KOLF2.1J is a human induced pluripotent stem cell (iPSC) line that was selected and characterized by the iPSC Neurodegenerative Disease Initiative (iNDI) as a community reference line to support large-scale, collaborative research, with particular emphasis on neurodegenerative disease modeling. The line was generated as a sub-clone of the parental KOLF2-C1 iPSC line, which was originally reprogrammed from fibroblasts obtained from a male donor of European ancestry under informed consent and appropriate ethical approvals. During sub-cloning, a heterozygous 19-bp deletion in ARID2 present in the parental line was corrected, yielding a clonally derived line with a low burden of deleterious variants and no known high-risk alleles for neurodegenerative disease, making it well suited as a neutral genetic background for disease modeling.KOLF2.1J demonstrates robust and reproducible pluripotency, high genomic stability in culture and after gene editing, efficient CRISPR editing, and reliable tri-lineage differentiation potential, with performance validated across multiple independent laboratories. The KOLF2.1J has been chosen as a high-quality, broadly applicable reference iPSC line suitable for adoption as a common cellular substrate to reduce inter-line variability and facilitate cross-laboratory data integration. To enable widespread use, KOLF2.1J and a growing collection of gene-edited isogenic derivative clones have been made openly available to the research community. More details can be found in Pantazis et al., "A reference human induced pluripotent stem cell line for large-scale collaborative studies", Cell Stem Cell (2022); doi: https://doi.org/10.1016/j.stem.2022.11.004.Building on this foundation, the present study extends the genomic characterization of KOLF2.1J using long-read and long-range sequencing to generate a complete, telomere-to-telomere reference assembly, together with matched long-read genomic, epigenetic and long- and short-read based expression data from differentiated derivative cell types. This work is described in the accompanying preprint Alvarez Jerez et al., "The complete genome of the KOLF2.1J reference iPSC line", bioRxiv (2026); doi: https://doi.org/10.64898/2026.03.06.710144. Data available through this dbGaP study include newly generated long-read sequencing data of the parental KOLF2.1J iPSC line and the differentiated cell lines (astrocytes, cortical neurons, NGN2-derived neurons, microglia, and oligodendrocytes) derived from the parental KOLF2.1J, along with corresponding expression data, and the assembled Y chromosome sequence. The assembled Y chromosome will be shared under controlled access for research use only, given the heightened re-identification risk associated with Y chromosome sequence data. The full diploid assembly, excluding the Y chromosome, is available through GenBank under BioProject PRJNA1478016.

  Study phs004798

• Cutaneous Squamous Cell Carcinoma: Integrating Germline and Somatic Alterations that Underlie Tumor Progression

  Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States, affecting over a million people annually, and with significant mortality due to metastasis. The overall scientific objective of this study is to identify and integrate novel tumor mutational data with previously characterized information on host genetic risk factors and clinical risk factors to better understand how cancer risk alleles contribute to the development of cSCCs capable of metastasis. We analyze 290 cSCCs (145 primary cSCCs) that progressed to metastasis and 145 non-metastatic primary cSCCs arising in the well characterized GERA cohort to provide a comprehensive landscape of genomic alterations in cSCCs. The aims of the study are: a) characterize the somatic genome and transcriptome of metastatic and non-metastatic cSCCs, b) integrate somatic mutational analysis with environmental exposure data, and c) develop a risk prediction tool for metastatic-cSCC that integrate genomic and clinical data.

  Study phs003681

• NHLBI TOPMed: San Antonio Family Heart Study (SAFHS)

  The San Antonio Family Heart Study (SAFHS) is a complex pedigree-based mixed longitudinal study designed to identify low frequency or rare variants influencing susceptibility to cardiovascular disease, using whole genome sequence (WGS) information from 2,590 individuals in large Mexican American pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for CVD, as well as to find novel low frequency or rare variants influencing susceptibility to CVD. WGS of the SAFHS cohort has been obtained through three efforts. Approximately 540 WGS were performed commercially at 50X by Complete Genomics, Inc (CGI) as part of the large T2D-GENES Project. The phenotype and genotype data for this group is available at dbGaP under accession number phs000462. An additional ~900 WGS at 30X were obtained through Illumina as part of the R01HL113322 "Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk" project. Finally, ~1,150 WGS at 30X WGS were obtained through Illumina funded by a supplement as part of the NHLBI's TOPMed program. Extensive phenotype data are provided for sequenced individuals primarily obtained from the P01HL45522 "Genetics of Atherosclerosis in Mexican Americans" for adults and R01HD049051 for children in these same families. Phenotype information was collected between 1991 and 2016. For this dataset, the SAFHS appellation represents an amalgamation of the original SAFHS participants and an expansion that reexamined families previously recruited for the San Antonio Family Diabetes Study (R01DK042273) and the San Antonio Family Gall Bladder Study (R01DK053889). Due to this substantial examination history, participants may have information from up to five visits. The clinical variables reported are coordinated with TOPMed and include major adverse cardiac events (MACE), T2D status and age at diagnosis, glycemic traits (fasting glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides). Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. PBMC derived gene expression assays for a subset of ~1,060 individuals obtained using the Illumina Sentrix-6 chip is also available from the baseline examination. The WGS data have been jointly called and are available in the current TOPMed accession (phs001215).

  Study phs001215

• Genes in Diabetic Retinopathy Project (DRCRnet-Genes)

  The "Genetics in Retinal Diseases Project" (Protocol-GEN) is an ongoing effort to create a repository of genetic material and clinical phenotype information as a resource for the research community, both public and private institutions. Blood samples are collected from consented participants from Diabetic Retinopathy Clinical Research (DRCR) Retina Network trials and sent to a qualified laboratory to harvest DNA and store the materials. This bioresource is available to the research community (e.g., government, academic centers, and industry) who may request samples, together with detailed clinical data, for genotypic analyses. When complete, the project will create a resource that combines high-quality genetic material and uniquely detailed phenotype information.The Network collaborated with Regeneron's Genetics Center for the sequencing of 2,084 samples, with both whole exome and genotype array data, as well as relevant phenotype data for the 8* completed studies (n = 2,074) are available for further analysis efforts. Of these, 850 samples of DME-only patients treated with anti-VEGF agents for 6 or 12 months were included in a GWAS study by the Network, in collaboration with the Mass Eye & Ear Infirmary (MEEI), for statistical analysis of the pharmacogenetics of treatment responses. Quality controlled genotypes from Illumina's Infinium Global Screening Array were imputed using the TOPMed reference panel. Both change in central subfield thickness (CST) and visual acuity (VA) were examined as co-primary phenotype endpoints, with several additional secondary outcomes and time to response. Linear and logistic regression were applied (PLINK2.0) to quantitative and dichotomous outcomes, respectively, on all samples and subpopulations (EUR, AFR, AMR) separately, adjusting for 10 genotype PCs, age, sex, HbA1c, diabetes type and duration, hypertension prior treatment, DR severity, baseline ETDRS and CST, and type/number of anti-VEGF agents received in 6 and 12 months. A cross-ancestry meta-analysis was performed on the 6-month time point using METAL. Replication of significant associations were pursued in a second independent sample set. To prioritize causal genes and pathways, gene and gene-set level association testing was performed using MAGMA. Colocalization analysis between expression and slicing QTLs (e/sQTLs) and significant GWAS loci was performed to further prioritize causal genes for genome-wide significant loci.Multiple loci were significant at a genome-wide significance (PPPIL3 and BICC1. Colocalization analyses with expression and splicing QTLs from GTEx tissues and retina further proposed putative causal genes for several loci. In replication analyses with a second, independent study, one locus on chromosome 5 passed genome-wide significance with a consistent direction of effect between the discovery cohort and replication cohort.Data available through dbGaP includes the entire genotype/sequencing dataset (2,084 samples), supporting documentation including SNP array and CNV calls derived from the sequencing, a linking table for accessing associated phenotype from the completed clinical trials (2,074 samples; URLs are listed in table below), and the GWAS/linkage results (851 samples). ProtocolProtocol DescriptionSamples AvailablePublic DatasetIIntravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema277DownloadMEffect of Diabetes Education during Retinal Ophthalmology Visits on Diabetes Control294DownloadSPrompt Panretinal Photocoagulation versus Intravitreal Ranibizumab with Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy196DownloadTA Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema460DownloadTXA Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema – Follow-up Extension Study5DownloadUShort-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy70DownloadVTreatment for Central-Involved Diabetic Macular Edema in Eyes with Very Good Visual Acuity423DownloadAAPeripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time250DownloadABIntravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative Diabetic Retinopathy99Download*Protocol AD (PROMINENT-Eye Ancillary Study, NCT03345901) ended prematurely due to low recruitment. Samples were collected but insufficient clinical data is available to create a phenotype dataset.

  Study phs004015

• Kids First: The Genomic Architecture of Hirschsprung Disease (HSCR)

  Hirschsprung disease (HSCR) is a male biased developmental disorder associated with a lack of innervation of the gastrointestinal tract. Genetic studies have been instrumental in understanding its multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity with variable penetrance and expressivity. At least 24 genes and 9 loci with pathogenic alleles (PAs) are known to underlie HSCR pathogenesis and explain 62% of its population attributable risk (PAR). Despite this heterogeneity, there is functional unity in HSCR: ~53% of HSCR PAs disrupt RET and EDNRB signaling in the developing enteric nervous system (ENS) in which 11 genes comprising a gene regulatory network control RET and EDNRB gene expression. We propose to identify the remaining 30% PAR by studying 857 unrelated HSCR cases, their 125 affected and 1,446 unaffected firstdegree relatives by whole genome sequencing to increase statistical power of gene discovery through improved detection of all types of coding and regulatory PAs. HSCR arises from cell autonomous defects in enteric neural crest cell precursors (ENCCs) affecting their proliferation, differentiation and migration in the ENS, functional studies that will guide our detection of novel genes.

  Study phs003662

• Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Related Studies: Other SPIROMICS data available include: SPIROMICS (main, phs001119); NHLBI TOPMed SPIROMICS (phs001927); Genetics and genomics (SPIROMICS Genetics Genomics, phs002399), and C4R SPIROMICS (phs002909).Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from SPIROMICS include: bronchial lavage, bronchial wash, oral wash, plasma, serum, sputum, and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Available Data: Data available for request include SPIROMICS I main study data as well as SPIROMICS Bridge phone call follow-up period data (period between SPIROMICS I NIH contract and SPIROMICS II grant).Objectives: The SPIROMICS study sought to identify homogeneous subgroups of COPD patients for targeted enrollment in future therapeutic clinical trials, as well as to identify and conduct preliminary validation of intermediate biological or clinical outcomes for use as clinical trial endpoints.Background: Chronic obstructive pulmonary disease (COPD) is a chronic, usually progressive, lung disease characterized by incompletely reversible airflow obstruction. At the time of the SPIROMICS study, COPD affected between 12,000,000 and 24,000,000 people in the US, with no proven medical therapies that significantly reduce mortality, other than supplemental oxygen and smoking cessation. COPD is also a highly heterogeneous disease. For example, cigarette smoke-induced chronic bronchitis and emphysema are subsumed within the COPD definition, despite histological and clinical differences. The recognition of COPD as a systemic disease that affects extra-pulmonary systems, including cardiovascular, sleep and muscle function, further complicates disease classification. Because of clinical and pathological heterogeneity, individual patient subtypes may benefit from unique therapeutic regimens. Thus the SPIROMICS study was initiated to facilitate the identification of important COPD phenotypes, based on disease pathophysiology and biomarkers that track key pathophysiologic processes, in order to focus research efforts and improve treatment options.Participants: Eligible participants were between 40 and 80 years of age, and included never-smokers, current and former smokers without obstructive lung disease, and current and former smokers with COPD. Never smoker was defined as less than 1 pack-year smoking history, and current or former smoker were defined as more than 20 pack-years smoking history. Lung function was also part of the eligibility criteria and was assessed by spirometry with or without inhaled bronchodilators. Non-smokers were required to have pre-bronchodilator FEV1 (forced expiratory volume in one second)/FVC (forced vital capacity) > 0.7 and FVC > LLN (lower limit of normal). Current or former smokers without obstructive lung disease were required to have post-bronchodilator FEV1/FVC > 0.7 and FVC > LLN. Current or former smokers with obstructive lung disease were required to have post-bronchodilator FEV1/FVC 50% predicted.Major exclusion criteria included non-COPD obstructive lung disease or a history of diseases or treatments likely to interfere with interpretation of study tests, BMI > 40 kg/m2 at baseline, hypersensitivity to or intolerance of the bronchodilators used in study assessments, and diagnosis of unstable cardiovascular disease. Design: SPIROMICS was a prospective cohort study that enrolled approximately 2,981 participants at twelve clinical centers over five years. Participants were distributed across four enrollment strata; never-smokers, smokers without COPD, smokers with mild or moderate COPD, and smokers with severe COPD.There were baseline (Visit 1) and three annual in-person follow-up visits (Visits 2–4). Participants also received quarterly follow-up calls to assess health status and determine if an exacerbation occurred. Visits 1, 2 and 4, included anthropometry, seated blood pressure, spirometry, 6-minute walk test, biological specimen collection, and a series of questionnaires. Information was collected on medical history, respiratory exposures and current medications. Visits 1 and 2 included a thoracic computed tomography (CT) scan at maximum inspiration and expiration. Clinical outcomes, including hospitalizations and deaths, were adjudicated centrally. The primary outcome measures up to month 36 were (1) morbidity measured by assessing acute exacerbations, (2) lung function by using spirometry and plethysmography to measure FEV1, FVC, FRC (functional residual capacity), and IC (inspiratory capacity), and (3) mortality. There were several key sub-studies involving SPIROMICS participants. The Repeatability and Replicate Sub-study enrolled 98 participants and repeated the entire baseline clinic visit, including the CT scanning, in order to quantify reliability and short-term within-person variability of study procedures and assay methods. In addition, sites collected blinded replicate samples on 5% of each specimen type at the Baseline, Year 1, and Year 3 visits. The Bronchoscopy Sub-study enrolled a total of 250 participants to undergo bronchoscopy with bronchoalveolar lavage, epithelial brushings and bronchial biopsies. The Exacerbation Sub-study enrolled a total of 214 participants that were followed prospectively and had biological samples (not available via BioLINCC) and clinical information collected at the time of an acute exacerbation.

  Study phs004568

• Identifying and Understanding Drivers of Chemoresistance in Small Cell Lung Cancer

  Using patient derived models of small cell lung cancer (SCLC), either the KEAP1 gene or the USP22 gene was deleted using lentiviral expression of a vector expressing CAS9 and single guide RNA (sgRNA) targeting KEAP1 or USP22. Control vector expressing models were also generated. RNA-Seq analysis was performed to compare gene expression in tumors growing in vivo, comparing KEAP1 deleted or USP22 deleted to control tumors under saline-treated and cisplatin/etoposide-treated conditions. Similar experiments were performed overexpressing USP22 or a control vector in a USP22-deleted patient derived xenograft model of SCLC. For USP22-deleted models, we also performed CUT&TAG analyses to examine the impact of USP22 loss on histone modifications.

  Study phs004087

• ChiLDReN/BA: Genetic Studies of Biliary Atresia in the Childhood Liver Disease Research Network

  Biliary atresia (BA) is a progressive necroinflammatory process initially involving the extra-hepatic biliary tree. Little is known about the factors that cause BA or the factors that influence disease progression. A variety of genetic, autoimmune, and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics as well as natural history.The Childhood Liver Disease Research Network (ChiLDReN) conducts two longitudinal and observational studies that include BA patients: Biliary Atresia Study in Infants and Children (BASIC) and A Prospective Database of Infants with Cholestasis (PROBE). Using samples from participants in these two protocols, we have formed the largest known data set of biliary atresia patients in the world. ChiLDReN is performing a series of genomic analyses, with subsequent analyses being released as subsequent versions of this registration, phs003356. Version 1 concerns PKD1L1.About the PKD1L1 Analysis (phs003356.v1): While multiple factors have been implicated in the perinatal biliary injuries that characterize BA, a definitive etiology has not yet been established. This study is part of a larger project to characterize the largest cohort of pediatric BA patients through whole-exome sequencing (WES). In this analysis, we examine the WES of those with various laterality defects to determine whether genetic factors could be identified to explicate the etiopathogenesis of BA in biliary atresia splenic malformation (BASM) syndrome. We specifically explored variations in the PKD1L1 gene, which recently has been identified in mouse models as playing a role in laterality.

  Study phs003356

• Retrovirus Epidemiology Donor Study-II (REDS II) Donor Iron Status Evaluation Study (RISE) (REDS_II_RISE -BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives The Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation Study (RISE) was designed to evaluate the effects of blood donation intensity on iron and hemoglobin (Hb) status, assess factors that could modify that relationship, and provide data to help formulate optimal whole blood donation frequency. Background Previous studies have shown that regular blood donors are at risk of iron deficiency. Also, a polymorphism in transferrin, which increases the likelihood that menstruating women will be iron deficient, and several genes for hemochromatosis were described in other previous studies. Findings from these studies lead to the possibility that genetic markers might define “at-risk” and “protected” donor groups with respect to iron depletion in blood donors. In addition, none of the previous donor studies had assessed the influence of racial/ethnic or socioeconomic factors, nor behavioral variables and dietary intake. Also, the availability of new tests of body iron status provided further opportunities to detect or prevent this problem. For these reasons, the National Heart, Lung, and Blood Institute's (NHLBI) Retrovirus Epidemiology Donor Study – II (REDS-II) program conducted the REDS-II Donor Iron Status Evaluation (RISE) whereby blood donors were followed prospectively for 15-24 months to provide an in-depth and contemporary evaluation of iron status in a US blood donor population.ParticipantsThe RISE study was a longitudinal multi-center study conducted between 2007 and 2009. All six REDS-II blood centers participated in the study: American Red Cross New England Region, Dedham, MA; the American Red Cross Southern Region, Atlanta, Georgia; the Blood Center of Wisconsin, Milwaukee, Wisconsin; the Hoxworth Blood Center/University of Cincinnati Medical Center, Cincinnati, Ohio; the Institute for Transfusion Medicine, Pittsburgh, Pennsylvania; and the Blood Centers of the Pacific, San Francisco, California. Two cohorts (2,425 whole blood or double red blood cell donors total) were established; one consisted of 888 first-time (FT) or reactivated (RA) donors and the other consisted of 1,537 frequent donors. The FT/ RA cohort consisted of men and women who had either never given blood before (FT) or had not given a donation in the two years before enrollment (RA). The frequent donor cohort consisted of men who had given the equivalent of ≥ 3 and women who had given ≥ 2 red blood cell units in the last year (or equivalent double-red blood cell donations). Male and females donors were recruited equally for each cohort. Most sites where donors were recruited were fixed rather than mobile sites. Only individuals who successfully donated whole blood or double-RBC units, were not deferred at their enrollment visit, and had agreed to donate frequently in the following 24 months were included in the study.DesignData on previous blood donation history; smoking history; diet; use of vitamins, supplements, and aspirin; and reproductive history (female donors) were collected through a self-administered enrollment questionnaire. Also, blood donation activity before and after enrollment, height, weight, country of birth, race and/or ethnicity, and highest educational level were compiled from blood center records and the donor information form that donors completed at the time of donation at the REDS-II centers. At enrollment, ferritin, soluble transferrin receptor (sTfR), and fingerstick and venous hemoglobin were determined. Models to predict two measures of iron deficiency, absent iron stores (AIS) and iron-deficient erythropoiesis (IDE), and hemoglobin deferral were developed. Absent iron stores (AIS) were indicated by a ferritin level of less than 12 ng/mL and iron-deficient erythropoiesis (IDE) by a log(sTfR/ferritin) value of 2.07 or greater, corresponding to the 97.5 percentile of the distribution of the log (sTfR/ferritin) in FT/RA males at enrollment. For hemoglobin deferral, a donor was deferred by current standards if their hemoglobin was ConclusionsA large proportion of both female and male frequent blood donors have iron depletion. Strong associations between higher prior donation intensity and a shorter time since last donation and iron depletion were observed. Iron depletion also developed in a high proportion of returning FT/RA donors (51% of females and 20% of male had IDE on follow up). Other than donation intensity and time since last donation, gender, weight, age, and the use of self-administered iron supplements were found to be important independent predictors of AIS and/or IDE. Time since last red cell donation was a highly significant factor for hemoglobin deferral as were black race, female gender and younger age in women. Reducing the frequency of blood donation is likely to reduce the prevalence of iron deficiency among blood donors, as might implementing routine iron supplementation.

  Study phs004507

• Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA

  Aberrant DNA methylation plays a critical role in tumorigenesis. While DNA methylation has been used for cancer detection and classification, DNA hemi-methylation, a novel epigenetic mark has not been analyzed extensively in cancer epigenomes. Here we report a strand-specific (ss) sequencing method (MeDIP-Seq) for plasma cell free (cf) DNA (sscf-MeDIP-Seq), which can analyze both symmetrically methylated DNA regions (DMRs) as well as hemi-methylated regions (DHMRs). Using the sscf-MeDIP-Seq method, we analyzed plasma cfDNA methylomes of 271 samples from subjects with liver cancer and brain cancer and from individuals without cancer (controls). Among them, 215 samples were chosen as the discovery cohort for the identification of DMRs and DHMRs specific in each subject group and for the training of machine learning models of multi-cancer detection (MCD) using DMRs, DHMRs and DMRs+DHMRs as inputs. These models were then used to predict the 56 samples in the validation cohort. We found that models trained with DMRs+DHMRs as inputs in general outperformed models trained with DMRs or DHMRs alone, with AUROC being 0.971, 0.981, and 0.99 in predicting control, liver and brain cancer samples in the validation cohort, respectively, by the DMR+DHMR-trained models.

  Study phs003462

• A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx): Acute Pain Trial

  This study description pertains to the ADOPT PGx Acute Pain Trial.The overall ADOPT PGx study was comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial (this study), the Chronic Pain Trial, and the Depression Trial. Participants could enroll in only one of the three trials. Trial-specific outcomes will be compared between participants in the intervention arm and control arms who have an actionable phenotype. Acute Pain Trial: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria were randomly assigned to either immediate pharmacogenetic testing and genotype-guided post-surgical opioid therapy (Intervention arm) or standard care and pharmacogenetic testing after 6 months (Control arm). Actionable phenotypes are defined as CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs) (i.e. CYP2D6 activity score ≤ 0.75) for the acute pain trial. This study includes approximately 1,610 participants with planned/elective surgery who are anticipated to start a pain control medication with existing CPIC guidelines after their surgery.

  Study phs004058

• NHLBI TOPMed: The Genetic Causes of Unexplained Cardiomyopathies (UNID_CM)

  This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. NHLBI TOPMed: The Genetic Causes of Unexplained Cardiomyopathies (UNID_CM) study performed whole genome sequencing (WGS) at usual and high read depths and transcriptome analyses (RNAseq) of blood (30x read depth) and cardiac tissues (90x read depth) from patients with Cardiomyopathies (Hypertrophic and Dilated). Samples were collected from patients with and without pathogenic mutations in cardiomyopathy genes. The goals of analyses were to advance the understanding of the molecular causes of heart diseases and to provide a robust collection of candidate molecules and mechanisms that cause or contribute to mutation-negative cardiomyopathy. We assessed the burden of these variants by comparison to variants described in publicly available mutation databases (e.g. CLINVAR for coding variants) and genomic sequence from unaffected (e.g. congenital heart disease subjects) and individuals with mutation-positive cardiomyopathies. We expect these analyses will define causes for mutation-negative cardiomyopathy. In addition, we predict that these “omic” datasets will substantially increase knowledge of the molecules, pathways, and mechanism that incite cardiac remodeling not only in cardiomyopathies but also in prevalent cardiovascular disorders.

  Study phs002382

• Genetics and Pathobiology of Disorders of Keratinization

  The goal of this study was to identify potential drivers of disorders of keratinization in human. Individuals diagnosed with disorders of keratinization were recruited with no exclusion criteria. Saliva or blood samples were taken from consented patients or family members and DNA harvested immediately. Whole exome sequencing was performed (150-bp paired end reads) to 80X coverage via an Illumina NovaSeq 6000 sequencer. Identification of germline mutations was performed using GATK.

  Study phs004172

• Sequencing of 3D Organoids Derived From Colorectal Cancer Patients

  This study focuses on the whole-exome sequencing (WES) of patient-derived organoids (PDOs) established from colorectal cancer (CRC) tumors collected at Columbia University. CRC remains a major cause of cancer-related mortality due to its metastatic progression and resistance to therapy. To model CRC at the patient level, we generated 3D organoid cultures from primary and metastatic tumors, preserving their genetic and phenotypic characteristics. The study cohort consists of 9 CRC patients with microsatellite-stable adenocarcinomas from the ascending, transverse, and descending colon, as well as the rectum, with differentiation statuses ranging from well to moderate and moderate-poor. Notably, for one patient, we generated organoids from both the primary tumor and matched liver metastases, allowing for a comparative analysis of tumor evolution. PDOs were derived from these tumors and subjected to WES at early passage to profile somatic mutations, copy number variations, and other genomic alterations to identify mutational signatures. Mutations identified in the PDOs were cross-referenced and confirmed with mutational data from the Columbia Solid Tumor Panel, which was conducted on all tumor tissues prior to organoid establishment. Molecular technologies employed include next-generation sequencing (NGS) for WES, enabling high-resolution characterization of the genomic landscape of CRC PDOs. WES of PDOs allowed us to classify tumor samples based on oncogenic mutations and mutation types, with a specific focus on PIK3CA. Notably, the efficacy of PI3Kα-specific pharmacologic inhibitors in suppressing organoid growth was dependent on the mutational status of KRAS and PIK3CA, underscoring the importance of genomic context in therapeutic response. The dataset available through dbGaP includes raw WES data from CRC PDOs.

  Study phs003965

• Genetic and Hormonal Contributions to Gene Expression in Immune Cells

  The origins of sex differences in human disease are elusive, in part because of difficulties in separating the effects of sex hormones and sex chromosomes. To isolate the effects of testosterone, estradiol, and sex chromosome complement (XX or XY) in humans, we implemented a four-state, cross-sectional study design of trans- and cisgender individuals, the former receiving exogenous testosterone or estradiol for at least a year as part of their gender-affirming medical care. This study design allowed us to compare four combinations of sex hormones and sex chromosomes in humans: XX individuals treated with exogenous testosterone (n=21), XY individuals treated with exogenous estradiol (n=13), untreated XX individuals (n=20), and untreated XY individuals (n=15). We chose to focus on the human immune system because it displays an impressively broad range of sex-differential biology. We collected blood samples from each individual and isolated PBMCs the same day. We performed 10X Genomics 3' single-cell RNA-sequencing (scRNA-seq) on PBMCs from the 69 individuals. We generated 150-bp paired end reads from a total of 358,426 cells (with an average of 48,007 reads/cell) and identified 18 distinct immune cell types. We found that testosterone, estradiol, and sex chromosome complement have unique, non-overlapping effects on PBMC cell abundances and gene expression.

  Study phs003860

• Processes Influencing Adult Health: Genotype and Epigenetic (DNA Methylation) for a Sample of Individuals who Experienced Poverty in Childhood

  This study evaluates the long-term consequences of childhood adversity on adult health. Individuals were aged 21-44 years and approximately half were women. During school-age years, these adults participated in research at Mt. Hope Family Center, including comprehensive assessments of psychological and interpersonal functioning and well as assessment of childhood adversity exposures. This follow-up study includes DNA methylation array data and SNP genotypes.

  Study phs004092

• Genetic and Genomic Analysis of Primary Human Chondrocytes

  Osteoarthritis (OA) is a common, degenerative joint disease characterized by the gradual breakdown of the cartilage in the joints. Despite osteoarthritis affecting over 500 million individuals, the lack of a comprehensive mechanistic understanding of the disease has greatly hindered the development of adequate treatment options. To address this, we generated RNA-seq, Hi-C, and ATAC-seq data in primary human chondrocytes treated with either PBS as resting or a fibronectin fragment (FN-f) to model the OA chondrocyte phenotype. We mapped expression quantitative trait loci and splicing quantitative trait loci, and performed colocalization with OA GWAS data to identify putative OA risk genes. Integration of ATAC-seq and Hi-C data provided insights into the regulatory mechanisms. This study revealed both expression-based and splicing-based OA risk genes, several of which had not been previously identified in chondrocyte studies.

  Study phs003581

• Functional Variant rs9344 at 11q13.3 Regulates CCND1 Expression in Multiple Myeloma with t(11;14)

  Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is the most significant susceptibility allele for t(11;14). We have found the G risk allele is enriched in both healthy individuals of African ancestry and African American individuals with MM. The overall aim of this study was to identify the mechanism behind why the G allele is enriched in t(11;14) MM. To reach this goal, we performed ATAC-seq from 100,000 CD138+ tumor cells from 26 patients with MM. In addition, we performed ChIP-seq using antibodies against H3K4me1, H3K27ac and H3K4me3 from 100,000 CD138+ tumor cells from 8 patients with MM. We used these data to evaluate whether the G allele of rs9344 is associated with elevated chromatin accessibility, H3K27ac and H3K4me3 in t(11;14) MM.

  Study phs003997

• Germline Mutations and Developmental Mosaicism Underlying EGFR-Mutant Lung Cancer

  We designed this study to examine the etiology of multiple lung tumors in EGFR-mutant non-small cell lung cancer patients who undergo surgical resection. Participants were 52-85 years old never or former smokers, who had at least 2 surgical lung tumor pathology specimens available in the Massachusetts General Hospital biobank, at least one of which had an EGFR mutation by routine clinical genotyping. 10 patients were selected, along with two patients from a family with an inherited EGFR-T790M mutation leading to multiple lung tumors. These patient tumor samples and matched normal lung samples were microdissected to collect DNA.In addition to obtaining clinical histories, we performed whole exome sequencing to evaluate the genetic profile of matched tumor and normal samples. The WES data are available on dbGaP. Our data showed increasing mutational burden and copy number alteration with increasing invasiveness, as compared to normal tissues, for the subset of samples that were assessed for tumor invasiveness. We also observed a range of numbers of shared mutations between tumors in a single patient, indicating different degrees of relatedness between lung tumors. We hope that this resource will help researchers understand non-small cell lung cancer presentations with multiple lung tumors. These data may aid in clinical decision making for such patients.

  Study phs003379

• Oncogenome of Kaposi Sarcoma

  Kaposi Sarcoma (KS) is an aggressive cancer caused by the Kaposi Sarcoma Herpesvirus (KSHV/HHV-8). Individuals with immunodeficiencies, exemplified by HIV, have an elevated risk of developing KS. However, understanding of the genetic factors contributing to KS progression is still limited. To explore potential genetic alterations in KS that could offer biological or therapeutic insights, whole exome sequencing was performed on 78 KS tumors and matching normal skin samples from 59 adults with KS (46 with HIV-associated KS and 13 with HIV-negative KS) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. Results showed a very low mutational burden in all samples except one (median = 11 mutations), which is the smallest number of mutations found across all 33 cancer types in The Cancer Genome Atlas (TCGA). No recurrent mutations were identified. Mutational signatures included impaired DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from a single clone. The number of genome copy alterations per genome was higher in tumors from individuals without HIV and those with advanced-stage disease. This suggests that lesions that take longer to develop may accumulate more alterations, although the overall number of alterations remains low compared to other cancers. These findings suggest that KS pathogenesis differs from other cancers, with KSHV viral infection and the expression of viral oncogenes being the primary drivers of carcinogenesis, rather than clonal oncogenic transformation arising from genetic alterations of cancer-related cellular genes.

  Study phs003897

• Acute Respiratory Distress Network (ARDSNet) Study 04 Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. BiospecimensAccess to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ALVEOLI include Plasma and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data Outcome data regarding organ failure free days are not available. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The ARDS Network 01/03 trials included an investigation of the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS (KARMA). The Ketoconazole arm of the KARMA study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. The objective of the ALVEOLI study was to compare clinical outcomes of participants with ALI and ARDS treated with a higher end-expiratory lung volume/lower FiO2 versus a lower end-expiratory lung volume/higher FiO2 ventilation strategy. The ALVEOLI study tested the hypothesis that mortality from ALI and ARDS would be reduced with a mechanical ventilation strategy designed to prevent lung injury from repeated collapse of bronchioles and alveoli at end-expiration. Background Most participants requiring mechanical ventilation for ALI and ARDS receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. PEEP levels higher than traditional levels may reduce ventilator-induced lung injury by decreasing the proportion of nonaerated lung and higher PEEP levels may allow arterial-oxygenation goals to be met at a lower level of inspired oxygen (FiO2). Participants A total of 550 participants were randomized to receive mechanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. Conclusions Participants with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes were statistically similar whether lower or higher PEEP levels are used. (Brower, et al., 1004; PMID: 15269312).

  Study phs003714

• Childhood Cancer Data Initiative (CCDI): Admixture Analysis of Acute Lymphoblastic Leukemia in African American Children: The ADMIRAL Study

  Children with substantial African ancestry are observed to have less than half the incidence of B-cell acute lymphoblastic leukemia (B-ALL) than children of other continental ancestries. The Admixture Analysis of Acute Lymphoblastic Leukemia in African American Children study (ADMIRAL) was designed to investigate genes and loci that explain the unique risk profile of African American children. Germline DNA samples were obtained from Children's Oncology Group frontline protocols, the Michigan BioTrust for Health, and various academic hospital ALL banks. Cases represented a diagnosis of B-ALL between the ages of 0-20 years, and controls were matched on birth year, sex, and maternal race/ethnicity. All participants have reported Black/African American race or substantial inferred African genetic ancestry. Altogether, 840 cases and 392 internal controls are included in this submission. All samples were genotyped on the Illumina Global Diversity Array 8v1. Phenotype information includes case/control status and reported sex.

  Study phs004222

• Characterization of Taste Genetics and Oral Microbiome in Early Childhood Caries

  This study included 538 participants under the age of 72 months, recruited between December 2017 and July 2022 from various community clinics across Winnipeg, Manitoba. Samples were collected from buccal swabs to sequence the taste-related genes. For the sequencing, 55 candidate genes were selected based on their roles in taste signal transduction, including receptors for bitter, sweet, umami, salt, sour, carbonation, and fatty acids, and some of their associated signaling proteins. DNA was isolated using the QIAamp Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. The candidate genes were amplified using primers designed for the Fluidigm platform to facilitate Illumina sequencing, ensuring that each amplified region covered approximately 250–300 base pairs for compatibility with 150 × 2 paired-end sequencing. The raw sequences of the candidate genes were mapped to the GRCh38 human reference genome using the BWA mapping tool. To identify the genetic variants in the candidate genes, the workflow adhered to the GATK best practice guidelines, with the exception of PCR duplicate removal, as this step is not recommended for targeted region amplification. A combined variant calling format (VCF) file containing genotyping information for the genes included in the study was generated for all 538 samples. This file was cleaned and filtered using VCFtools. Quality control steps included filtering for a Phred quality score greater than 25, missing data less than 50%, and a sequencing depth greater than 5. SNPs were annotated using BCFtools with the human dbSNP138 database, and variant annotation was performed using SnpEff based on the human genome version, GRCh38. This VCF file will be available from dbGaP. In this study, we found significant associations of variants in the bitter taste receptor gene TAS2R60 (rs35195910), sodium ion transport gene SCNN1D (rs111819661), and phospholipase gene PLCB2 (rs2305645) with early childhood caries.

  Study phs004182

• CIDR: Elucidating Epigenetic Mechanisms of Racial/Ethnic Disparities in Pancreatic Cancer

  This is a nested case-control study of 689 pancreatic cancer cases and 807 matched controls from the Multiethnic Cohort Study (MEC) (see dbGaP phs002183), a diverse prospective cohort of >215,000 African American, European American, Japanese American, Latino, and Native Hawaiian individuals from Hawaii and Los Angeles. The objective of this study is to identify blood DNA methylation markers of pancreatic cancer susceptibility and to examine whether epigenetics can partially explain the racial and ethnic disparities of pancreatic cancer. Our specific aims are: 1) to identify multiethnic epigenetic markers of pancreatic cancer risk, 2) to assess whether epigenetics improves the prediction of pancreatic cancer across race and ethnicity, and 3) to evaluate whether epigenetics mediates the association between known modifiable risk factors and pancreatic cancer. The findings from this study are expected to identify potential ethnic-specific carcinogenic processes and elucidate the determinants of racial and ethnic disparities in pancreatic cancer.

  Study phs003735

• Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT-BioLINCC)

  Data Access NOTEPlease refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. BiospecimensAccess to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from TOPCAT include Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The TOPCAT trial evaluated the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function. Background Many patients with heart failure have a normal, or near-normal, left ventricular ejection fraction (LVEF). Such patients share similar signs and symptoms as patients who have heart failure and a reduced LVEF, as well as an impaired quality of life and a poor prognosis. However, at the time of TOPCAT, the benefit of medical therapies for heart failure were limited to those with a reduced LVEF. Due to a lack of favorable evidence from clinical trials, clinical guidelines offered no specific recommendations for the management of heart failure in patients with preserved LVEF, except for attention to coexisting conditions. Among patients with heart failure and a reduced LVEF and those with myocardial infarction complicated by heart failure and left ventricular dysfunction, mineralocorticoid receptor antagonists have been shown to be effective in reducing overall mortality and hospitalizations for heart failure. In small mechanistic studies involving patients with heart failure and preserved left ventricular function, mineralocorticoid receptor antagonists improved measures of diastolic function. However, rigorous testing was needed regarding their effect on clinical outcomes in patients with preserved LVEF. Therefore, the TOPCAT trial was initiated to determine whether treatment with spironolactone, an aldosterone antagonist, would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved LVEF. Participants A total of 3445 participants were enrolled, with 1722 assigned to the spironolactone group and 1723 assigned to the placebo group. Among these, 2464 participants were enrolled via the hospitalization stratum and 981 were enrolled via the BNP stratum. Design TOPCAT was a phase 3, multicenter, international, randomized, double-blind, and placebo controlled trial. Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio. Randomization was stratified according to whether the patient met the criterion for previous hospitalization or BNP elevation. The baseline visit included assessment of socio-demographics, physical characteristics, medical history, lifestyle factors, laboratory measures, electrocardiography variables and health-related quality of life and functional status. Study drugs were initially administered at a dose of 15 mg once daily, which was increased as tolerated to a maximum of 45 mg daily during the first four months after randomization. Subsequent dose adjustments were made as required and subjects continued to receive other treatments for heart failure and co-existing illnesses. Measurement of potassium and creatinine levels was required within 1 week after a change in the study-drug dose and at each scheduled study visit. Follow-up visits to monitor symptoms, medications, and events and to dispense study drug were scheduled every four months during the subject's first year on the study, and every six months thereafter. The mean follow-up interval was 3.3 years in each study group. Repository blood and urine samples were collected at the baseline and 1 year visits from consenting subjects. The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary endpoints included all-cause mortality, hospitalization for heart failure management, new onset of diabetes mellitus or atrial fibrillation, and quality of life. A subset of subjects also participated in the Echocardiography or Echocardiography and Vascular Stiffness ancillary studies. Echocardiography, and additionally tonometry in the Echocardiography and Vascular Stiffness study, were performed at baseline and at either 12 or 18 months following randomization. If the subject was already enrolled in the TOPCAT trial at the time the ancillary study was initiated, but had not yet reached the 18 month visit, baseline was determined via a retrospective analysis performed on any echocardiographic images completed within 60 days prior to TOPCAT enrollment and no tonometry was performed if applicable. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. However, the drug reduced the secondary endpoint of heart failure hospitalization incidence.

  Study phs003665

• National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS)

  NIAGADS is an NIH controlled-access data repository that collaborates with researchers around the world to facilitate data access and sharing for genomic and associated omics data related to Alzheimer's Disease (AD), Alzheimer's Disease Related Dementias (ADRD), as well as healthy aging. Serving as the data coordinating center for the Alzheimer's Disease Sequencing Project (ADSP), NIAGADS hosts all ADSP-generated whole-exome, whole-genome and associated phenotypes. Other data types hosted by NIAGADS include genotype SNP arrays, functional omics, fluid biomarkers, aggregated imaging data (such as volumetric data for brain regions of interest), and summary statistics. In adherence with NIH security best practices and genome data sharing policies, NIAGADS supports data access requests through review by an NIH-appointed and registered Data Access Committee. Data stored within NIAGADS cannot be requested via dbGaP. Data requests must go through the NIAGADS Data Sharing Service (DSS) via the following NIAGADS url: https://dss.niagads.org/. Questions related to the request of data should be directed to the NIAGADS admin team at: niagads@pennmedicine.upenn.edu. DSS is a FISMA certified platform built by a team of data scientists at the University of Pennsylvania to support the request and access of AD/ADRD data by qualified researchers internationally. Questions related to the use of data hosted in the DSS should be directed to the Portal admin team at: help@niagads.org.

  Study phs004180

• Frontotemporal Dementia and Related Disorders: Transcriptomic Profiling, Biomarker Discovery, and Mechanistic Insight

  Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) lie on a disease spectrum, characterized by overlap in diagnosis, pathology, and underlying genetics. The most prominent of the overlapping genetic causes is a repeat expansion in the gene C9orf72, which is the most common cause of both FTD and ALS. Our study aims to identify the transcriptomic signature of C9orf72-related FTD and ALS by studying post-mortem human brain tissue. Specifically, here we integrated long-read and short-read RNA sequencing data to comprehesively characterize the human frontal cortex, evaluating FTD and ALS patients with the C9orf72 repeat expansion, FTD and ALS patients without the C9orf72 repeat expansion, and controls. Our analysis consisted of transcript classification and annotation, differential gene and transcript analysis, and splicing burden analysis. In total, we found over 1,000 differentially expressed transcripts, including nearly 200 of which that were classified as novel compared to a human reference. Notably, some of these differentially expressed transcripts contained cryptic exons present in genes known to be regulated by TDP-43, like STMN2, while others have not been previously shown (e.g., DRC1). As use to the research community, we have created a shiny application web browser (link: __) that allows for exploration of all transcripts that we detected.

  Study phs004442

• Genetic Studies of Glomerular Diseases

  This ongoing study investigates the genetic basis of idiopathic nephrotic syndrome (INS) and related glomerular diseases, including focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). We hope to identify genetic factors associated with disease susceptibility and clinical heterogeneity.Eligible participants include individuals of any age, sex, gender, race, or ethnicity with a clinical diagnosis of primary nephrotic syndrome. Individuals with known secondary causes of nephrotic syndrome, including diabetes- or obesity-associated glomerular disease, or kidney biopsy findings consistent with alternative primary or secondary glomerular diseases (e.g., membranous nephropathy or autoimmune kidney disease), were excluded. Written informed consent was obtained from all participants or legal representatives.Participants were recruited primarily through the Division of Nephrology at Columbia University Irving Medical Center and the Division of Pediatric Nephrology at Morgan Stanley Children's Hospital, with additional enrollment through collaborating centers in Europe and South America.

  Study phs004810

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659

• Investigations of Genetic Variation in Families Affected by MUTYH-Associated Polyposis

  Defects in the Base-Excision Repair gene, MUTYH, are known to increase colorectal cancer risk through a recessive Mendelian pattern and raise mutation rates in both normal somatic and germline mammalian cells. In this study, we employed whole genome sequencing (WGS) of fifteen human individuals (representing 4 related families) at 50X coverage to examine germline de novo mutation rates in a large family with pathogenic MUTYH mutations and a history of colorectal cancer. We used an in vitro cell line assay to determine the family's genotype (p. Y179C/V234M, transcript NM_001128425) partially attenuates MUTYH's function. The children of mothers affected by the biallelic pathogenic genotype were associated with a moderate increase in the C>A mutation rate, but this effect was determined to be lower than previously reported mutator effects for other biallelic pathogenic MUTYH genotypes. No similar mutation rate increase was found in children of fathers with the same genotype despite calculating that we should have adequate power to detect such a mutator effect, indicating that MUTYH's role in repairing oxidative stress might be more significant in female reproductive aging than in males. We used a combination of in vitro cell line assays and bioinformatics pipelines to assess the impact of the MUTYH genotype on germline mutation rates. The study design ensures that sufficient statistical power was available to detect mutator effects in both maternal and paternal lineages. The sequencing data generated from this study include single sample genotype files derived from WGS, focusing on germline DNA. The phenotypic data at individual level and sequence data can be accessed by authorized users, facilitating further exploration of the relationship between MUTYH pathogenic variants and colorectal cancer risk.

  Study phs003554

• Interrogating Gene Regulation During Human Cortical Development

  Our study investigates the regulatory function and evolutionary origins of the fastest evolved genomic regions in the human genome termed Human Ancestor Quickly Evolved Regions (HAQERs), during human cortical development. Single-cell RNA sequencing (scRNA-seq) data were generated from human cortical progenitor cells from 4 individuals spanning the second trimester of development, subjected to pooled CRISPR interference (CRISPRi) perturbations targeting 50 HAQERs using an all-in-one lentiviral vector. Bulk ATAC-seq was performed using the same 4 human subjects to prioritize the 50 accessible HAQERs to be silenced. Single cell RNA sequencing libraries were generated using the 10x Genomics chromium high-throughput 3′ gene expression platform under lentiviral transduction with high MOI, low MOI, and low MOI under Wnt pathway stimulation. To enable assignment of individual donors in multiplexed single-cell experiments, genotypes were obtained using the Illumina Global Screening Array.

  Study phs004522

• Normal Pressure Hydrocephalus

  Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. 

  Study phs002296

• Contextual and Health Behavior Effects on Epigenetic Aging Among Africans in the Family and Community Health Studies

  The Family and Community Health Studies (FACHS) is a longitudinal examination of health and health related behaviors in African American families. The original study cohort consisted of 867 African American parent-child dyads from Georgia and Iowa who were ascertained in cooperation with local school districts. The key inclusion criteria for participating in the study were the presence of an adolescent in the 5th grade (approximately 10-11 years old) who self-identified as African American (i.e., the Target) and the participation of a primary caretaker (PC) for the Target. The clinical and biological data included in this collection are from the Target (i.e., FACHS-T) portion of these studies of these African American parent-child dyads. The initial wave of behavioral assessments of the FACHS-T subjects was conducted in 1997-98 (Wave 1), with seven subsequent ascertainments, Wave 2 (1999–2000), Wave 3 (2002–2003), Wave 4 (2005–2006), Wave 5 (2007–2009), Wave 6 (2010–2011), Wave 7 (2014–2016) and Wave 8 (2019-2021). Full interviews were obtained at each wave of the study with the exact content of the wave varying as a function of developmental age. These interviews of the FACHS-T subjects collected a wide variety of data including the following: perceived discrimination; socioeconomic status; substance use exposure; common internalizing and externalizing disorders such as depression, substance use, and conduct disorder; school efficacy; peer support and perceived parenting practices. Biological sampling of the FACHS-T subjects was conducted at three time points. Saliva DNA was collected at Wave 5 while full phlebotomy was conducted at Waves 7 and 8. The genome wide methylation data listed below is derived from the whole blood DNA samples collected at Wave 8 and Wave 9. The genome wide genotyping data was determined using DNA from the Wave 7 samples. The clinical and biological data available herein are those from 309 FACHS-T subjects who participated in both Wave 7 and Wave 8, and who consented for deposition of their data in dbGAP.

  Study phs003723

• Genetic Investigations of Attention-Deficit/Hyperactivity Disorder

  Design and Aims:We conducted whole-exome DNA sequencing on 152 parent-child trios (456 individuals total) that included a child meeting DSM-IV or DSM-5 criteria for ADHD along with both biological parents to identify rare de novo damaging DNA variants associated with ADHD risk. Mutation rates were compared between 147 ADHD trios and 780 unaffected control trios. We aimed to identify specific ADHD risk genes by combining the de novo trio data with rare variant data from an independent case-control cohort.Population Information:ADHD trios were collected from four sites. The 780 control trios were unaffected siblings from the Simons Simplex Collection who scored in the normal range on the Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) ADHD subscale.Molecular Technologies:Whole-exome DNA sequencing was performed on the ADHD trios using the IDT xGen V1 or Agilent SureSelect All Exon V7 capture and the Illumina NovaSeq6000 sequencer. Control trios were previously sequenced with the NimbleGen SeqCap EzExomeV2 capture and Illumina HiSeq 2000 sequencer. Joint variant calling was performed for all trios. Rare de novo variants with allele frequency Principal Findings:We found a 1.67-fold enrichment of rare de novo damaging variants and a 1.93-fold enrichment of ultra-rare de novo damaging variants in ADHD cases vs controls. By integrating the de novo data with an independent case-control cohort, KDM5B was identified as a high-confidence ADHD risk gene (FDR=0.04). Three potential risk genes were also identified. Twenty-three genes with ultra-rare damaging de novo variants in ADHD overlapped with previously reported risk genes for other neuropsychiatric conditions. Exploratory analyses showed enrichment of these genes in early neurodevelopmental pathways.

  Study phs003647

• Center for Common Disease Genomics (CCDG) - Cardiovascular: Multiethnic Cohort

  The genetic basis of cardiovascular disease in individuals of non-European ancestry remains largely unknown. Availability of ethnically diverse study populations is essential to investigate the underlying causes of disease.The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex, inherited diseases. The Multiethnic Cohort (MEC) of the University of Hawaii Cancer Center and the University of Southern California comprises primarily five ethnic groups: Caucasians, Japanese Americans, Native Hawaiians, African Americans and Latinos. This study contains whole genome sequence data derived from participants in the MEC cohort identified as having early onset coronary artery disease.

  Study phs003499

• Acute Respiratory Distress Syndrome Clinical Network: Fluid and Catheter Treatment Trial (ARDSNet FACTT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-FACTT include plasma, DNA, and serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: This study evaluated the benefits and risks of Pulmonary Artery Catheters (PACs) in patients with established acute lung injury in a trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol.Background: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary organ perfusion.Participants: This randomized study compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology. Design: Participants were randomly assigned to a strategy involving either conservative or liberal use of fluids with concealed allocation in permuted blocks of eight with the use of an automated system. Participants were simultaneously and randomly assigned to receive either a pulmonary-artery catheter or a central venous catheter in a two-by-two factorial design.Conclusions: There was no significant difference in the primary outcome of 60-day mortality; however, the conservative strategy of fluid management was associated with improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non-pulmonary organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (NEJM June 15, 2006; Vol 354, No. 24, pp 2564-75; NEJM May 25, 2006; Vol 354, No. 21, pp 2213-24)

  Study phs004165

• Cellular Basis for Genetic Susceptibility to Neurodevelopmental Disorders

  In contrast to syndromic CNVs such as the 17p11.2 deletion in Smith-Magenis syndrome, which mostly occur de novo and are highly penetrant, more recent studies have identified another class of CNVs that are frequently inherited and associated with variable expressivity. We previously identified a 520-kb deletion on chromosome 16p12.1 that was associated with multiple neurodevelopmental outcomes, including intellectual disability/developmental delay (ID/DD), schizophrenia, autism, and epilepsy. This variant is inherited in >95% of cases from carrier parents manifesting neuropsychiatric features. We also found that affected children with the deletion were more likely to carry another large CNV or rare deleterious mutation elsewhere in the genome compared to carrier parents. Thus, while the 16p12.1 deletion confers significant risk for a range of disorders, the ultimate phenotypic trajectory is determined by variants in the genetic background. Functional assessment of the deletion would therefore provide a novel cellular paradigm for how the same variant confers susceptibility to distinct neurodevelopmental disorders. We used induced pluripotent stem cells (iPSCs) reprogrammed from peripheral blood mononuclear cells (PBMC) from three families with the 16p12.1 deletion, each including two or more affected children who manifest severe ID/DD or autism, carrier parents with neuropsychiatric features, and unaffected non-carrier parents. We generated neural progenitor cells (NPCs) and differentiated cortical neurons from 12 individuals from three families, including affected children with either severe ID or autism, carrier parents with neuropsychiatric features, and non-carrier parents, and assessed the impact of the deletion during different timepoints of neuronal development.

  Study phs002403

• Functional Genomics and Tumor Microenvironment Analysis Reveal Prognostic Biological Subtypes in Mantle Cell Lymphoma

  Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations are consistently associated with poor prognosis, whereas ATM mutations correlate with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters are identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis reveals enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFNα, TNFα) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrates enrichment of CD4⁺ T cells with high expression of exhaustion markers and a dominant population of myeloid cells skewed toward an M2-like phenotype. Spatially, TP53-perturbed MCLs are immune-infiltrated but exhausted, while ATM-perturbed cases remain immune-cold with dense tumors. Functional analysis shows that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-perturbed MCL.

  Study phs003849

• Role of Microglia Somatic Mutations in Neurodegenerative Diseases

  Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer's Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

  Study phs002213

• Developmental Genotype Tissue Expression (dGTEx) Project

  Lay DescriptionThe aims of the Developmental Genotype-Tissue Expression (dGTEx) Project are to study changes in gene expression and regulation that affect both normal growth and impact health and disease in a pediatric cohort, spanning birth to age 18. Children are often underrepresented in clinical research, and most genomics studies primarily use adult donors and tissues that lack insight into specific developmental changes that occur in childhood. dGTEx researchers are studying genes from different tissues obtained from across pediatric development to create a database that researchers can use to study how genes change throughout childhood. The dGTEx project also includes a study of the donor consent process to help ensure that the goals of the project and participation in the project effectively address the concerns and expectations of donors and their families in the study.Scientific DescriptionDespite considerable variation in expression patterns across tissues and individuals, these patterns are relatively stable throughout adulthood, where most human gene expression studies have been performed. The changes in gene expression that occur during postnatal development are largely unstudied, yet lead to important milestones in health and disease, such as the onset or cessation of growth spurts or puberty, and the development of both childhood specific diseases, as well as diseases that manifest much later in life.The goal of the developmental Genotype-Tissue Expression (dGTEx) project is to establish a resource database in which to study the relationship between gene expression and other molecular phenotypes in multiple relatively healthy reference neonatal, pediatric, and adolescent tissues, building on the original (adult) GTEx project.This study aims to recruit at least 120 donors with a total of ~30 donors per age group, in each of 4 developmental windows: Infant: 0-2 yo, Early Childhood: 2-8 yo, Pre-pubertal: ~8-12.5 yo, Post-pubertal: ~12.5-18 yo. Donor tissue collection protocols have been developed to maximize the diversity of quality tissues recovered, with a minimum of 20 to a maximum of 74 different tissue sites sampled per donor.The pediatric study is complemented by the Non-Human Primate Developmental GTEx (NHP-dGTEx) project which will also catalog and analyze transcriptional profiles across a wide variety of tissues at multiple developmental stages from two species of non-human primates: Macaca mulatta (rhesus macaque), an old world monkey, and Callithrix jacchus (common marmoset), a new world monkey. The main goal of the project is to create a parallel data resource of tissues from individuals at each of 6-8 developmental stages, to enhance understanding of developmental changes and allow cross-species, temporal comparisons of gene expression, and cell-type specific gene and epigenetic data across different stages of primate development.

  Study phs003838

• CIDR: Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos

  This study aims to investigate the genetic contribution to the increased risk of acute lymphoblastic leukemia (ALL) in children of Hispanic/Latino ethnicity. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed on childhood ALL cases and controls of self-reported Hispanic/Latino ethnicity from two studies: 1) the California Childhood Leukemia Study (CCLS), and 2) the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). This study will provide genome-wide SNP array data from Hispanic/Latino children, contributing to studies of the genetic etiology of childhood ALL and cancer health disparities. It will also provide data from childhood ALL cases and controls from a Hispanic/Latino population outside of the United States (i.e., Mexico). Genetic data were generated by the Center for Inherited Disease Research. Samples were genotyped using the Illumina Global Diversity Array GDA-8v1-0. Individual level genotype data will be available through dbGaP. Note that for a small number of genotyped cases in the MIGICCL study, it was later found that these were not ALL cases but were either acute myeloid leukemia (AML) or non-acute leukemia. Additional available data include demographic and birth-related variables, and patient-related data including age-at-diagnosis and leukemia immunophenotype and molecular subtypes.

  Study phs003953

• Targeted Long-Read Sequencing Enables Comprehensive Analysis of the Genetic and Epigenetic Landscape of Inherited Myopathies

  This study investigated the utility of targeted Oxford Nanopore Technologies (ONT) long-read sequencing (LRS) for the diagnosis of inherited myopathies. A targeted ONT LRS assay was applied to a cohort of myopathy participants with and without previous genetic diagnoses. Our results demonstrate that this assay provides comprehensive genetic and epigenetic characterisation of inherited myopathies. At the time of dbGaP submission, disease causing variants had been identified a number of genes (DUX4, GIPC1, DGUOK, NOTCH2NLC, RILPL1, ABCD3, LAMA2 and CAPN3) in a group of previously undiagnosed genetic myopathy participants. The ONT LRS assay also identified known pathogenic variants in a number of genes (CAPN3, CACNA1S, RYR1, MT-TL1, CNBP, DMD, DUX4, SMCHD1) in a group of positive control participants with previously known genetic diagnoses.

  Study phs004623

• Acute Respiratory Distress Network (ARDSNet) Study 02 Late Steroid Rescue Study (LaSRS) (ARDSNet-LaSRS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-LaSRS include BAL Slides, Bronchial Lavage, and Plasma. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: Since previous reports suggested that corticosteroids may improve survival, this project was developed as a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS.Background: Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death.Participants: There were 180 participants.Conclusions: The results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. (NEJM April 20, 2006; Vol 354, No. 16, pp 1671-84).

  Study phs003769

• Honolulu Heart Program (HHP-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from HHP include DNA, plasma, serum, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The initial objectives of the Honolulu Heart Program were to: 1) estimate morbidity and mortality from coronary heart disease and stroke among Japanese men in Honolulu; 2) compare morbidity and mortality from coronary heart disease and stroke among Japanese men in Japan, Honolulu, and San Francisco; 3) investigate relationships among risk factors, coronary heart disease, and stroke in Japanese men in Honolulu; 4) compare distributions of risk factors among men in Japan, Honolulu, and San Francisco, and relate similarities and differences in risk factors to the occurrence of disease in these areas and in other populations, including Framingham and Puerto Rico; 5) conduct an autopsy study, and to relate pathological findings to morbidity and mortality data; and 6) investigate relationships between risk factors and pathological evidence of atherosclerosis and its complications.Background: The Honolulu Heart Program was initiated in 1965 by the NHLBI as a prospective study of environmental and biological causes of cardiovascular disease among Japanese Americans living in Hawaii. This population was known to have low incidence of coronary heart disease and higher incidence of stroke. The study provided opportunities to investigate relationships among disease frequencies, pathologic findings, and disease predictors in the cohort and to compare the findings in this population with those in other populations, especially cohorts of Japanese men resident in Japan or the U.S.Participants: There were 8006 participants.Design: The study began in 1965 with the first examination of a cohort of 8,006 Japanese-American men residing on the island of Oahu, Hawaii who were born during the period 1900-1919. The first examination was completed in 1968 and was followed by the initiation of a second examination that same year. Three subsequent sub-examinations (Lipoprotein Exams I, II and III) were conducted between 1970 and 1982 to collect lipid measurements on a subset of those who participated in Exam II. The fourth examination of surviving members of the original cohort was conducted during 1991-93 and collected data on 3,741 men. Morbidity and mortality follow-up continues through grant and contract-supported efforts, and the current HHP dataset includes events through 1998.

  Study phs003907

• Framingham Heart Study-Cohort (FHS-Cohort) - BioLINCC

  Data Access NOTE Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Related Studies Other Framingham data available include: Imaging studies (Framingham Heart Study-Cohort (FHS-Cohort)-Imaging, phs003593), Genetics and genomics (Framingham Cohort, phs000007), Collaborative Cohort of Cohorts for COVID-19 Research (C4R): (Framingham Heart Study, phs002911), and as a component of the Sleep Heart Health Study (SHHS-BioLINCC, phs003637). Available Data Original cohort: data now include examination data from the first 32 clinical exams, selected ancillary data, and event follow-up through 2018. Offspring/Omni1 cohort: Data available include Framingham Offspring examination data from the first 9 clinical exams and selected ancillary data and event follow-up through 2019. Also included are the first 4 exams from the OMNI 1 cohort. Third Generation/Omni2/New Offspring Cohort: Data available include Framingham Generation 3 examination data from the first 3 clinical exams, selected ancillary data and event follow-up through 2019. Also included are the OMNI 2 and New Offspring (NOS) cohorts. A genetic pedigree is not provided for the Framingham phenotype only data. Objectives The objectives of the Framingham Study are to study the incidence and prevalence of cardiovascular disease (CVD) and its risk factors, trends in CVD incidence and its risk factors over time, and familial patterns of CVD and risk factors. Other important objectives include the estimation of incidence rates of disease and description of the natural history of cardiovascular disease, including the sequence of clinical signs and systems that precede the clinically recognizable syndrome and the consequences and course of clinically manifest disease. Background Original cohort: The original cohort of the Framingham Study began in 1948 under the U.S. Public Health Service and was transferred under the direct operations of the new National Heart Institute, NIH, in 1949. Participants were sampled from Framingham, Massachusetts, including both men and women. This was the first prospective study of cardiovascular disease and identified the concept of risk factors and their joint effects. Offspring/Omni1 cohort: With the aging of the Framingham cohort and with interest in familiar aggregation and heritability, a new cohort consisting of the offspring of the original cohort was sampled. Spouses of offspring were also included. This new sample, began enrollment in 1971 and constituted a second generation of participants, permitting new assessment of risk factors and outcomes, and provided a resource for the genetic analyses which were yet to come. The Offspring participants have had repeated examinations, though at typically longer intervals than the original cohort. Third Generation/Omni2/New Offspring Cohort: Thirty-one years after enrollment began for the second generation of the Framingham Heart Study (Framingham Offspring Study), Framingham investigators began enrolling adults with at least one parent enrolled in the Offspring study into the Framingham Generation 3 cohort. The addition of the third generation was expected to facilitate investigation of secular trends in risk factors and indicators of health and disease within families, to enhance statistical power to detect genetic and environmental determinants of complex diseases, and to clarify how subclinical cardiovascular disease predicts occurrence of overt clinical events. Participants Original cohort: At entry to the study in 1948-1952, the study recruited 5,209 men and women, ages 28-62 years, living in Framingham, MA. Offspring/Omni1 cohort: 5,124 men and women, ages 5-70 years at entry consisting of offspring of the original Framingham cohort (and spouses of the offspring). In 1994, the Omni Cohort 1 enrolled 507 men and women of African-American, Hispanic, Asian, Indian, Pacific Islander and Native American origins, who at the time of enrollment were residents of Framingham and the surrounding towns. Third Generation/Omni2/New Offspring Cohort: 4095 men and women, almost all who self reported their ethnicity as white, ages 19+ years at entry, with at least one parent in the Framingham Offspring study, participated in the Gen III cohort. The New Offspring Cohort enrolled spouses of Offspring participants that were not otherwise enrolled and had at least two biological children participating in Gen III. 103 New Offspring Spouses (47 men and 56 women) participated. The OMNI 2 cohort enrolled additional ethnically diverse participants, including many individuals related to the participants of Omni Cohort 1 and also individuals unrelated to Omni Cohort 1 members for a total of 410 new participants. Design The cardiovascular disease conditions under investigation include coronary heart disease (angina pectoris, myocardial infarction, coronary insufficiency and sudden and non-sudden death), stroke, hypertension, peripheral arterial disease and congestive heart failure. Original cohort: The Framingham Study is a longitudinal investigation of constitutional and environmental factors influencing the development of CVD in men and women. Examination of participants has taken place every two years and the cohort has been followed for morbidity and mortality over that time period. Offspring/Omni1 cohort: By 1975, a sample of 5,124 men and women, consisting of offspring of the original Framingham cohort (and spouses of the offspring) had participated in the study. Additional studies of these subjects have continued under research contracts. Third Generation/Omni2/New Offspring Cohort: The children of Offspring Cohort participants were initially identified who would be 20 years of age or older by the end of the enrollment period. A higher priority for recruitment was assigned to individuals who belonged to large extended families, in order to complement phenotypic and genotypic information already obtained from prior generations. The baseline examination was begun in 2002 and completed in 2005.

  Study phs003594

• Genomic Landscape of Colorectal Cancer in a Multi-Ancestry Cohort

  Elucidating the tumor mutational landscape of colorectal cancer (CRC) in admixed and ancestrally diverse populations is essential to enable precision medicine advancements that benefit individuals of all backgrounds. This study draws from the Latino Colorectal Cancer Consortium (LC3) and other prior initiatives to characterize and examine the somatic mutational patterns of colorectal tumors in Hispanic/Latino/Latina patients (henceforth referred to as Latino) as compared to other racial and ethnic populations. It includes paired tumor-normal whole-exome sequencing from 718 patients with primary CRC (128 Latino and 469 non-Latino individuals) to investigate the associations between somatic mutational features and both self-reported ethnicity and genetic ancestry. Somatic mutations and inherited variants were called, and global genetic ancestry proportions (African, Asian, European, Native American) were estimated from inherited variants using ADMIXTURE based on reference samples from the 1000 Genomes Project (1KGP) and the Population Architecture using Genomics and Epidemiology (PAGE) Study. Associations between genetic ancestry and gene-level mutational status, microsatellite instability status, and tumor mutational burden were estimated using logistic regression, after adjusting for age at diagnosis, sex, tumor location, and stage.

  Study phs003464

• dbGaP Collection: NIH Autism -omics Studies

  Autism Spectrum Disorders (ASD) are early onset neurodevelopmental syndromes characterized by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. ASDs afflict ~1% of the human population, and represent a major public health burden. Evidence for the etiology of ASD has consistently pointed to a strong genetic component, though the genetic architecture is indisputably complex. This dbGaP Collection consists of studies that include GWAS, sequencing (targeted, exome, whole genome), transcriptomics, etc, across many different cohorts. Many of the datasets have been curated and harmonized with NDAR prior to submission to dbGaP. Researchers who request and are approved to access this collection will be granted access to all related substudies in dbGaP as well as all NDAR data. Individual level genomics data will only be available for download through dbGaP along with minimal phenotype and pedigree information. Detailed phenotype and available imaging data related to these same research subjects are available for query and download within NDAR. The NDAR GUID will allow individual genomic data to be associated with all NDAR data collected for those subjects.

  Study phs000764

• Genetic Modifiers of Duchenne Muscular Dystrophy

  The primary determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or permits the expression of a partially functional protein. However, even in the complete absence of dystrophin, variability in disease severity is observed, with candidate gene studies implicating several genes as potential DMD modifiers. This study undertakes a comprehensive genome-wide search for modifier loci influencing disease severity in DMD patients. The availability of subjects for such studies remains limited, resulting in modest sample sizes that challenge the GWAS design. To address this, we have implemented measures to minimize heterogeneity within the dataset at the dystrophin (DMD) gene itself, adopting a conservative approach to DMD mutation classification to limit the possibility of residual dystrophin expression. Additionally, the study employed statistical methods that are well-suited to smaller sample sizes, including the use of a novel linear regression-like residual for time to ambulatory loss and the application of evidential statistics, specifically the Posterior Probability of Linkage Disequilibrium (PPLD), to assess trait-SNP associations in the GWAS framework. With a sample size of 419 patients, this study has identified multiple candidate genetic modifier loci. The molecular data available in dbGaP includes 2,562,265 directly genotyped variants in 419 people using the Illumina Infinium Omni2.5Exome-8 Beadchip assay, achieving a genotyping rate of 0.998. The phenotypic data comprises age at ambulatory loss, steroid status, DMD gene mutation, and the PPLD value from the time-to-event (TE) phenotype.

  Study phs003680

• NCTN: A Phase 1/2 Study of CPX-351 (NSC# 775341) Alone followed by Fludarabine, Cytarabine, and G-CSF (FLAG) for Children with Relapsed Acute Myeloid Leukemia (AML) (AAML1421)

  Study ID: AAML1421NCT Number: NCT02642965 Children's Oncology Group (COG)Submitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: A Phase 1/2 Study of CPX-351 (NSC# 775341) Alone followed by Fludarabine, Cytarabine, and G-CSF (FLAG) for Children with Relapsed Acute Myeloid Leukemia (AML) (AAML1421)Trial Description: This phase I/II trial studies the side effects and best dose of liposome-encapsulated daunorubicin-cytarabine when given with fludarabine phosphate, cytarabine, and filgrastim and to see how well they work in treating younger patients with acute myeloid leukemia that has come back after treatment (relapsed) or is not responding to treatment (is refractory). Liposome-encapsulated daunorubicin-cytarabine is made up of two chemotherapy drugs, cytarabine and daunorubicin hydrochloride, and works to stop cancer cell growth by blocking the cells from dividing. Drugs used in chemotherapy, such as fludarabine phosphate and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Filgrastim may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving liposome-encapsulated daunorubicin-cytarabine followed by fludarabine phosphate, cytarabine, and filgrastim may be a better treatment for patients with relapsed acute myeloid leukemia and may cause fewer side effects to the heart, a common effect of other chemotherapy treatments for acute myeloid leukemia. Clinical data presented in the following publication(s): PMID 32401633 Disease type(s): Hematopoietic Neoplasm/Leukemia - Acute Myeloid LeukemiaClinical Dataset(s) included: NCT02642965-D1 (PMID 32401633): There is 1 dataset for AAML1421's primary publication, PMID 32401633. The NCT02642965-D1 dataset is a patient level dataset (single row per patient) containing patient characteristics, cytogenetic categories, tumor response, survival, neutrophil count recovery, toxicity, residual disease status, and pharmacokinetic data for eligible pediatric acute myeloid leukemia (AML) patients enrolled on the AAML1421 clinical trial.You are encouraged to view the PDF data dictionaries found in the "Documents" tab of the dbGaP study page, which may contain additional information regarding the data or the associated publication(s).

  Study phs004160

• Risk Factors for Asymptomatic Diverticulosis

  Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

  Study phs003556

• Establishment of an iPSC Repository Derived from Healthy Volunteers

  Understanding the interaction between genetic variation and epigenetic variation remains a challenge due to the confounding role of environmental factors. We propose that human induced pluripotent stem cells (iPSCs) are an excellent model to study the relationship between genetic variation and epigenetic variation while controlling for consistent environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data of six iPSC lines and three iPS-derived cell types (NSC, Motor Neuron, Monocyte) from three healthy donors. We found that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in the differentiated cells. Additionally, cell-type is a stronger source of epigenetic variation than genetic variation, highlighting that humans are far more similar than they are different, regardless of genetic background. Further, we have elucidated a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell-types in which they may be acting.

  Study phs003649

• Prevention and Early Treatment of Acute Lung Injury Network - Reevaluation of Systemic Early Neuromuscular Blockade (PETAL ROSE-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Data Update: The data available for request now include additional Long Term Outcome data and ancillary data on DNA complexes..Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ROSE include Plasma, DNA, Whole Blood, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets in patients with moderate-to-severe ARDS.Background: It has been well established that the approaches used for the application of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) can affect survival and outcomes after discharge from the intensive care unit (ICU). A large, multicenter trial conducted a decade before this study reported that the early administration of a 48-hour infusion of neuromuscular blockade in patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen [Pao2] to the fraction of inspired oxygen [Fio2] of Participants: There were 1006 participants.Design: PETAL-ROSE was a multicenter, unblinded, randomized trial of patients with moderate-to-severe ARDS. Participants were randomly assigned in a 1:1 ratio to receive 48 hours of continuous neuromuscular blockade with concomitant deep sedation (intervention group) or to receive usual care without routine neuromuscular blockade and with lighter sedation targets (control group).Patients in the intervention group who were not under deep sedation at baseline were deeply sedated within 4 hours after randomization. Subsequently, patients in this group received an intravenous bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg per hour for 48 hours. After the 48-hour trial intervention period, decisions regarding further use of neuromuscular blockade, including the choice of agent, were left to the discretion of the treating clinician. Neuromuscular blockade could be stopped early if the patient met the criteria for freedom from mechanical ventilation (Fio2 ≤0.40 and PEEP ≤8 cm of water) for at least 12 hours. All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy for up to 5 days after randomization. Assessors who were unaware of the group assignment interviewed surviving patients or their proxies at 3, 6, and 12 months after randomization. The primary end point was in-hospital death from any cause at 90 days (in-hospital was defined as the time in the trial hospital plus transfer to another hospital, including the time in long-term acute care facilities). Conclusions: After the second interim analysis, the decision to stop the trial for futility was made independently by the data and safety monitoring board.In critically ill patients identified shortly after the diagnosis of moderate-to-severe ARDS, the addition of early continuous neuromuscular blockade with concomitant deep sedation did not result in lower mortality than a usual-care approach to mechanical ventilation that included lighter sedation targets.

  Study phs003878

• ​​Rare Genetic Variants and Severe COVID-19 in Previously Healthy Admixed Latin American Adults​

  This study investigates the contribution of rare genetic variants to the progression of severe COVID-19 in young and middle-aged adults without pre-existing health conditions. The cohort included 161 Brazilian patients aged 18 to 60 years who were hospitalized in intensive care units due to life-threatening SARS-CoV-2 infection. Whole-genome sequencing (WGS) was performed to detect rare variants, followed by a targeted prioritization of loci previously linked to severe COVID-19 outcomes. The analysis identified 104 rare and potentially deleterious variants across 79 genes, with ultra-rare alterations most frequently observed in MUC5AC, IFNA10, ZNF778, and PTOV1. Seventeen novel variants were discovered, several predicted to be pathogenic or indicating strong intolerance to loss-of-function (LoF) mutations. Clinically, carriers of prioritized rare variants showed an increased incidence of acute respiratory distress syndrome (ARDS) (p = 0.027, OR = 2.59), and those with variants in highly LoF-intolerant genes had a fourfold higher mortality risk (p = 0.0084, OR = 4.04).This represents the first comprehensive genomic analysis of severe COVID-19 in a previously healthy Latin American population, emphasizing the relevance of identifying population-specific rare variants associated with disease severity.

  Study phs004369

• Identification of a Type 1 Diabetes-Associated T Cell Receptor Repertoire Signature from the Human Peripheral Blood

  Type 1 Diabetes (T1D) is a T-cell mediated disease with a strong immunogenetic HLA dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones, yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed participants across three cross-sectional cohorts, including T1D individuals, and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in T1D individuals. We leveraged deep learning to identify T1D-associated TCR subsequence motifs that were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of T1D individuals. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and groundwork for TCR-based diagnostics and therapeutics.

  Study phs003979

• Atherosclerosis Risk in Communities Study (ARIC-BioLINCC)

  Data Access NOTE:Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. At present, the ARIC sIRB has determined that ARIC data cannot be shared with for-profit entities.Related Studies Other ARIC data available include: Imaging studies (ARIC-Imaging), Genetics and genomics (ARIC, phs000280.v8.p2), Collaborative Cohort of Cohorts for COVID-19 Research (C4R): ARIC (phs002988.v1.p1), and as a component of the Sleep Heart Health Study (SHHS-BioLINCC, phs003637.v1.p1). Available Data Data available for request include ARIC v1-v8 examination cycles, collated annual follow-up communication data for contact years 2-32, and follow-up for mortality, heart disease, and stroke events through 2019. Also included are data from ancillary studies. Objectives The objectives of ARIC are to: 1) investigate associations of factors, including those not previously measured in cohort studies, with prevalence of atherosclerosis and incidence of CHD, clinical stroke and other cardiovascular diseases; and 2) measure cardiovascular disease occurrence and trends and relate these to community levels of, and changes in, risk factors, medical care and atherosclerosis. Background At the time of project initiation, the NHLBI had long recognized the need for longitudinal studies to identify the biochemical and physiological markers and specific environmental factors which place individuals at high risk for the major atherosclerosis diseases. The development of reliable ultrasound examination of peripheral arteries enhanced the expected benefit of such studies. Community surveillance planning began for ARIC in response to recommendations of the 1978 NHLBI Workshop on the Decline in CHD Mortality and has been extended in its purpose to evaluate the large geographic differences in U.S. mortality. Participants Black and white men and women, age 45-64 at entry; sample size: 15,792. Design ARIC is a large-scale, long-term prospective study that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women from four geographically diverse communities. The project has two components: community surveillance of morbidity and mortality; and repeated examinations of a representative cohort of men and women in each community. The community surveillance involves abstracting hospital records and death certificates and investigating out-of-hospital deaths. The representative cohorts include approximately 4,000 persons from each community. Community surveillance data includes detailed hospital record abstraction, ECG tracings, and event adjudication. Data from out-of-hospital events in the community include physician, informant, and coroner questionnaires as well as death certificate data and event adjudication. Community surveillance ended in 2014.Cohort participants were examined four times at three year intervals between 1987 and 1998, and have been continuously contacted annually to update their medical histories. Atherosclerosis was measured by carotid ultrasonography. Risk factors studied include: blood lipids, lipoprotein cholesterols, and apolipoproteins; plasma hemostatic factors; blood chemistries and hematology; sitting, supine and standing blood pressures; anthropometry; fasting blood glucose and insulin levels; ECG findings; cigarette and alcohol use; physical activity levels; dietary aspects; and family history. Clinic visits were restarted in 2011 with ARIC visit 5.

  Study phs003738

• Rare and Atypical Diabetes Network (RADIANT)

  The Rare and Atypical DIAbetes NeTwork (RADIANT) is a multicenter prospective cohort study that is dedicated to characterizing (discovering and defining) rare and atypical forms of diabetes. Individuals will be screened for evaluation of suspected atypical diabetes of unknown origin. Among the pool of evaluated individuals, those found to have a known form of diabetes will be excluded from further study. The remaining participants will be prioritized for genetic/genomic analysis and further testing. Primary Objectives: • Identify and enroll individuals and families with undiagnosed rare and atypical forms of diabetes. • Determine the etiologic basis of the metabolic disorder among individuals and families with novel forms of rare and atypical diabetes. • Understand the pathophysiology of individuals and families with novel forms of rare and atypical forms of diabetes. RADIANT has three distinct stages. Stage 1: Participants complete a consent form and a questionnaire to determine the potential for having atypical forms of diabetes. Participants identified as potentially having atypical forms of diabetes based on questionnaire responses are asked to provide a blood sample to test for islet autoantibodies and complete additional questionnaires. The RADIANT Adjudication Committee, which is comprised of a team of experts in diabetes, assesses the data collected in Stage 1, then selects and prioritizes participants to proceed to Stage 2 and 3 for Whole Genome Sequencing (WGS) and other testing. Stage 2: Genetic screening of participants for known forms of monogenic diabetes. Participants will consent for this stage of the study, complete a family history questionnaire, and have blood collected for DNA and RNA extraction, storage, and analysis. Whole genome sequencing (WGS) is performed on all DNA samples. If WGS does not identify a pathogenic/likely pathogenic variant in a known monogenic diabetes gene that is thought to explain the participant's diabetes, RNA Sequencing is performed at Baylor College of Medicine. Stage 3: Deeper phenotyping of all participants who proceed to Stage 3. Participants visit a study clinic to consent and complete Stage 3 procedures which include: an Oral Glucose Tolerance Test (OGTT), additional blood collection, a detailed physical exam, and additional questionnaires. The work of the Discovery Team is expected to be an iterative process analyzing all data collected up to this point in the study to understand the significance of novel variants. In some instances, the Discovery Team may determine that enrollment of the Proband's family members is necessary. Family members with suspected atypical diabetes will follow the same study procedures as described above. Affected and unaffected family members may also be enrolled for Sanger Sequencing or trio WGS. The Discovery Team may also recommend additional optional procedures to better characterize the participant's form of diabetes.Clinical and deeper phenotyping data can be requested from the NIDDK Central Repository (https://doi.org/10.58020/1wxp-dw53).

  Study phs004543

• Genomic Sequencing of Ewing Sarcoma

  Pediatric Ewing sarcoma is a pediatric cancer that primarily arises from the bone. It is characterized by chimeric fusions of the EWS gene and an ETS family transcription factor. In this study, we performed massively parallel sequencing of a larger collection of Ewing sarcoma tumors to define the genomic landscape of this disease. We found that these tumors are among of the most genetically normal cancers currently characterized. There was also a marked absence of recurrent mutations in immediately targetable signaling transduction pathway genes. In this study we answer outstanding questions about ETS transcription factor expression, effects of treatment on mutational burden in Ewing sarcoma tumors, and describe patterns of tumor evolution. We also found that loss-of-function mutations in STAG2 were present in approximately 15% of Ewing sarcoma tumors and loss of STAG2 expression was associated with disease metastasis in this patient cohort.

  Study phs000804

• A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx): Depression Trial

  This study was comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial, and the Depression Trial (this study). Participants could enroll in only one of the three trials. Trial-specific outcomes will be compared between participants in the intervention arm and control arms who have an actionable phenotype.Depression: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria were randomly assigned to either immediate pharmacogenetic testing and genotype-guided anti-depressant therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). Actionable phenotypes are defined as CYP2C19 ultra-rapid metabolizers (UMs), rapid metabolizers (RMs) and poor metabolizers (PMs) or CYP2D6 ultra-rapid metabolizers (UMs) and poor metabolizers (PMs) for the depression trial. This study includes approximately 1470 participants seen in primary care or psychiatry clinics who are already prescribed or anticipate to be prescribed an SSRI with existing CPIC guidelines.

  Study phs004069

• The Genetics of Food Cue Reactivity in Children

  This study aimed to investigate genetic factors related to appetite, eating in the absence of hunger and brain reward response to food cues in a convenience sample of pre-adolescent children taken through two studies (A and B). The study involved genome-wide genotyping using the Illumina Global Screening Array. The study found an obesity polygenic risk score related to parent-reported appetitive traits in children, The study also found that FTO was related to eating in the absence of hunger and brain reward response to food cues. Available data include genotypes, measured height and weight, appetitive traits, consumption, brain reward response to food cues, and sociodemographic variables.

  Study phs003550

• Acute Respiratory Distress Network Early Versus Delayed Enteral Feeding to Treat People with Acute Lung Injury or Acute Respiratory Distress Syndrome (ARDSNet EDEN-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-EDEN include bronchial lavage, plasma, DNA, and urine. Please note that use of biospecimens in genetic and non-genetic research is subject to a tiered consent. Objectives: To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days (VFDs) and decrease gastrointestinal intolerances compared with initial full enteral feeding. Background: Mechanically ventilated patients cannot eat normally and if not fed for long periods become malnourished. Because malnutrition is associated with poor outcomes in critically ill patients, artificial nutrition is often provided, especially in those with acute lung injury (ALI) and with expected longer duration of mechanical ventilation. When feasible, enteral nutrition targeting full caloric needs has been advocated over parenteral nutrition. However, feeding intolerance and common care practices often serve as practical barriers to reaching recommended goals. Although confounded by indication and severity of illness, several observational studies have shown improved clinical outcomes, including fewer infections, shorter duration of mechanical ventilation, and lower mortality for patients receiving a higher percentage of calculated caloric needs. Nonetheless, the best timing, formulation, and amount of enteral nutrition remain unknown. Participants: A total of 1,000 participants were enrolled. Design: Participants were randomized, stratified by site and presence of shock at enrollment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation. The initial 272 patients were also simultaneously randomized to a separate trial (the OMEGA study) comparing a nutritional supplement containing omega-3 fatty acids and antioxidants with an isocaloric, isovolemic control in a 2 × 2 factorial design.The designated feeding strategy was initiated within 6 hours of randomization and continued until death, extubation, or day 6. The care of mechanically ventilated patients still receiving enteral feedings after day 6 was managed according to the full feeding strategy in both groups. In extubated patients who then required reintubation, enteral nutrition was restarted and managed according to the study protocol.In the full-feeding group, enteral nutrition was initiated at 25 mL/h and advanced to goal rates as quickly as possible. Gastric residual volumes were checked every 6 hours while enteral feeding was increased. Patients randomized to the initial trophic-feeding group had enteral nutrition initiated at 10 mL/h (10-20 kcal/h) for the first 272 patients who also received the omega-3 or control supplement (240 mL volume per day). After the data and safety monitoring board stopped the OMEGA portion of the factorial design, the initial trophic feeding rate was changed to 20 kcal/h to approximate the calories that had been delivered in the OMEGA study. Gastric Residual Volumes (GRVs) were checked every 12 hours during trophic feeding. In patients randomized to trophic feeding, enteral nutrition was advanced to full-energy feeding rates following the same protocol used for the full-feeding group if they were still receiving mechanical ventilation at 144 hours. Conclusions: There was no difference between groups with regard to the primary end point, VFDs to day 28. There also were no differences in 60-day mortality, organ failure−free days, ICU-free days, or the incidence of infection between groups. Similarly, there were no differences between groups in VFDs or survival when analyzed by body mass index category or when subsets of patients with shock or more severe lung injury (acute respiratory distress syndrome) were examined.JAMA. 2012 Feb 22;307(8):795-803

  Study phs004168

• Hemochromatosis and Iron Overload Screening Study (HEIRS-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from (HEIRS) include Buffy Coat, DNA, Dried Buffy Coat, Lymphocytes, Plasma, and Serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The HEIRS Study evaluated the prevalence and genetic and environmental determinants and potential clinical, personal, and societal impact of iron overload and hereditary hemochromatosis in a multi-center, multiethnic, primary care-based sample of adults.Background: Hereditary iron overload, or hemochromatosis, is a common inherited disorder resulting from overabsorption of dietary iron. Excess iron is deposited in body tissues, and can accumulate to toxic levels over time causing damage in multiple organ systems. If untreated, these conditions may lead to death. Evidence suggests that early diagnosis and treatment can prevent disease manifestations and enable normal life expectancy. Thus, hemochromatosis may be suitable for detection and intervention through primary care screening strategies; however, much remains to be learned about the penetrance and expression of the known gene variants, HFE C282Y and H63D, associated with hemochromatosis. Iron overload and hereditary hemochromatosis have not been as extensively studied in racial/ethnic groups other than Caucasians.Participants: The initial screen phase included 102,000 adults recruited over a 2-year period from 5 North American Field Centers (approx. 51% white, 24% African American, 11% Asian, 11% Hispanic, and 3% unidentified race; 63% are female and 37% are male).Design: During the initial screen phase in 2001-2002, participants were recruited from primary care practices and blood-drawing laboratories. Blood specimens were tested for transferrin saturation (TS), serum ferritin (SF), and HFE C282Y and H63D genetic variants. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload. Those participants with elevated iron levels and/or C282Y homozygosity, their family members, and frequency-matched control participants completed an examination that obtained data on personal and family medical history, lifestyle characteristics, genetic counseling and assessment of ethical, legal and social implications of screening, as well as clinical and biochemical measures. A separate randomized study examined the acceptability of genotypic or phenotypic (biochemical) screening for hemochromatosis.The majority of HEIRS participants have a consent limited to research on iron related disorders. Conclusions:Findings include: 1) transferrin saturation (TS) and serum ferritin (SF) mean levels differ across race/ethnic groups; 2) HFE C282Y variant does not account for these levels in non-Caucasians (Adams et al, NEJM 352:1769-78, 2005); and 3) there is similar participant acceptance for genotypic as for phenotypic testing (Anderson et al, 2005: PMID: 16247294).

  Study phs004477

• Multiple Myeloma Clinical Targeted Sequencing of Patient Samples

  Purpose: Molecular diagnostics for the risk stratification of patients with multiple myeloma (MM) have languished in the area of cytogenetics and fluorescence in situ hybidization (FISH). However, here we present the case for next generation sequencing of MM patient samples to not only identify high-risk markers, but also mutations and deletions relating to immunomodulatory drugs (IMiDs), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. Experimental design: CD138+ cell selected samples (n=134) from bone marrow aspirates from patients with multiple myeloma were sequenced using a targeted panel in a clinical diagnostics laboratory. Data were analyzed for high-risk markers, treatment-related resistance mechanisms, and precision medicine targets to guide the future treatment of patients in the clinic. Results: High-risk markers including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of CDKN2C, and deletion or mutation of TP53 were identified in 15% of newly diagnosed myeloma patient samples. At relapse, alterations in the cereblon degradation pathway were found in 24.3% of IMiD treated patients. Deletions of 4p (CD38) were also enriched in patients who received anti-CD38 treatment (P=0.03) which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17 encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Conclusions: Targeted sequencing of multiple myeloma patient diagnostic samples can be used for risk stratification, and also to monitor and adjust treatments as resistance mechanisms evolve.

  Study phs003908

• Genetic and Clinical Determinants of Telomere Length

  Numerous studies have established connections between leukocyte telomere length (LTL) and genetics and health. However, these studies have concentrated on specific diseases or GWAS analyses. We sought to explore the interplay between LTL, genomics, and human health by examining two vast patient populations obtained from the Vanderbilt University and Marshfield Clinic bio banks. These patient populations were linked to genomic and phenomic data from medical records. Our GWAS validated 11 genetic loci already associated with LTL, along with two novel loci in SCNN1D and PITPNM1. Using PheWAS, we identified 67 different clinical phenotypes connected with either short or long LTL. Our research showed that various diseases linked with LTL were related to each other but were largely independent of LTL genetics. Additionally, we found that age of death was related to LTL regardless of length. Individuals with very short LTL ( 1.5 SD) died 1.9 years earlier than those with average LTL. This aligns with our PheWAS results that show diseases associated with both short and long LTL. Finally, we discovered that the genome (12.8%), age (8.5%), the phenome (1.5%) and sex (0.9%) all together explained 23.7% of LTL variance. These findings underscore the need for additional research to understand the multifaceted connections between TL biology and human health over time.

  Study phs003273

• 10x Multiome from Human Fetal Heart

  We hope to uncover the genetic basis of congenital heart disease by examining how genetic variants, especially those in non-coding regions, influence heart development. To achieve this goal, our research team created a single-cell atlas of human fetal heart development. The study population consists of 41 structurally normal fetal hearts spanning 6 to 22 weeks post-conception. We profiled close to 750,000 using single-cell RNA sequencing and ATAC sequencing technologies via the 10x Genomics Multiome platform.The molecular technologies employed allowed for simultaneous analysis of gene expression and chromatin accessibility at the single-cell level. This approach identified numerous distinct cell types and states within the developing heart, offering detailed insights into gene activity and enhancer usage during critical stages of heart development.Principal findings include the characterization of diverse cell populations and the identification of specific gene expression patterns and regulatory elements active during heart formation. This high-resolution atlas provides valuable insights into how genetic variants may disrupt normal heart development, particularly those in non-coding regions that affect gene regulation.

  Study phs003778

• Blood and Marrow Transplant Clinical Trials Network A Trial of Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Lenalidomide Maintenance for Patients With Multiple Myeloma (BMT CTN-0702-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To compare the use of tandem autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide maintenance, AHCT plus four cycles of lenalidomide, bortezomib, and dexamethasone (RVD) followed by lenalidomide, and AHCT and lenalidomide only in improving outcomes for patients with active multiple myeloma (MM).Background: At the time of this trial, initial myeloma reductive therapy followed by high-dose melphalan plus AHCT with long-term lenalidomide was the standard of care for patients newly diagnosed with MM in the United States. Despite substantive improvements in outcomes with the addition of lenalidomide, most patients still experienced disease progression and ultimately died as a result of the disease. Several approaches to further improve outcome after initial AHCT have been investigated but incremental benefit compared with maintenance therapy remains to be determined. This trial was initiated to assess whether the additional interventions of second AHCT or RVD consolidation to AHCT and lenalidomide further improve outcomes.Participants: Patients with symptomatic MM who were 70 years old or younger, had a Karnofsky score equal to or greater than 70, received at least two cycles of any regimen as initial systemic therapy without disease progression, and were within 2 to 12 months of the first dose of initial therapy were eligible.758 patients were enrolled. 247 patients were randomly assigned to the AHCT/AHCT + lenalidomide arm, 254 patients to the AHCT + RVD + lenalidomide arm, and 257 patients to the AHCT + lenalidomide arm.Design: The BMT CTN-0702 study was a Phase III multicenter trial. All patients were randomly assigned in a 1:1:1 manner at the time of enrollment, which occurred within 7 days before the first high-dose melphalan conditioning regimen. Random assignment was stratified by disease risk and transplantation center. High-risk MM was defined by presence of high β2-microglobulin, presence of cytogenetic abnormalities, or aneuploidy. Patients without cytogenetic analysis available and low β2-microglobulin level (≤5.5 mg/L) or with deletion 13 detected by fluorescence in situ hybridization were classified as standard risk.All enrolled patients were to receive high-dose melphalan (200 mg/m2) followed by mobilized autologous peripheral-blood stem-cell infusion (minimum 2 × 106 CD34+ cells/kg). Subsequent therapy was based on random assignment at the time of enrollment. The second phase of therapy started between 60 and 120 days after the first AHCT, once patients had sufficiently recovered. Patients randomly assigned to a second transplantation received high-dose melphalan (200 mg/m2) followed by autologous peripheral-blood stem-cell infusion. Patients randomly assigned to RVD consolidation received four cycles of lenalidomide 15 mg/d on days 1 to 14; bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle; and dexamethasone 40 mg per day on days 1, 8, and 15. After their initial interventions, all patients received lenalidomide starting at 10 mg per day for 3 months and increasing to 15 mg per day. Dose adjustments for toxicity were permitted. Maintenance therapy was initially designed to be given for 3 years to all patients. An amendment expanded use of lenalidomide to continue until toxicity, disease progression, or withdrawal of consent.Quality of life was assessed using the Short Form 36 and Functional Assessment of Cancer Therapy-Bone Marrow Transplant at baseline and yearly.The primary study end point was progression free survival at 38 months.Conclusions: Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with multiple myeloma did not improve progression free survival or overall survival. Single AHCT and lenalidomide should remain as the standard approach for this population.

  Study phs004692

• Gabriella Miller Kids First Pediatric Research Program in Bladder Exstrophy, Epispadias, Complex (BEEC)

  Urogenital anomalies account for 20-30% of prenatally detected structural defects. Bladder Exstrophy Epispadias Complex (BEEC) describes a subset of anomalies with a spectrum of developmental defects ranging from a mild form of epispadias, to classic bladder exstrophy, to omphalocele, exstrophy, imperforate anus, spinal anomalies (OEIS) complex. Patients with BEEC suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy.

  Study phs002173

• Center for Common Disease Genomics [CCDG] Neuropsychiatric: Autism Spectrum Disorder (ASD) – Whole Exomes

  The National Human Genome Research Institute (NHGRI) has funded a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Called the Centers for Common Disease Genomics (CCDG), this initiative will explore a range of diseases with the ultimate goal of 1) undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of the genomic architecture underlying common, complex inherited diseases, 2) understanding how best to design rare variant studies for common disease, and 3) developing resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community. The initial focus of the CCDGs will be in cardiovascular disease (early-onset coronary artery disease, atrial fibrillation, hemorrhagic stroke), neuropsychiatric disease (epilepsy, autism), and autoimmune/inflammatory disease (type 1 diabetes, inflammatory bowel disease). The Broad Institute is one of four selected CCDG project centers. The goal of the Autism Spectrum Disorder (ASD) program is to work together to utilize dramatic new advances in DNA sequencing technology to reveal the genetic architecture of autism through comprehensive examination of the exotic sequence of all genes.

  Study phs002502

• The Collaborative Study on the Genetics of Alcoholism (COGA)

  COGA is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results, are included for a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3. As part of COGA, a set of informative families was selected to have Genome-Wide Association data obtained within families. Genotyping was performed using the Illumina Human OmniExpress array 12.VI to genotype 2,282 subjects selected from 118 densely affected families. Genotyping was performed at the Genome Technology Access Center at Washington University School of Medicine in St. Louis. In addition, we also included genotypes for subjects (n=275 subjects) from these 118 families who were genotyped in a previous case-control GWAS using the Illumina 1M array. For quality control purposes, 51 of the 275 subjects were genotyped again on the Illumina Human OmniExpress array at the Washington University School of Medicine core facility.In addition, exome sequencing data on a subset of individuals with GWAS were added in version 2 (v2). For v2, a subset had 30X Whole Genome Sequencing (WGS) as part of the NIDA Sequencing Initiative. The subset contained two distinct sets: Sibling pairs where one sibling had at least two dependence diagnoses in the set (alcohol, cannabis, cocaine, and opioid), and the other had none, and non-related Case-Control pairs matched for age and ethnicity where the cases had alcohol and at least 2 other dependence diagnoses and controls had none. After sequencing, some sibling pairs are re-classified as half siblings. Three VCF files (small variants, structural variants, and copy number variations) are provided. Additional substance use variables are made available in v2. We note that the full sample data are deposited in four dbGaP submissions and the sequenced samples are split across all four: CIDR: Collaborative Study on the Genetics of Alcoholism Case Control Study [phs000125]. GWAS data on cases (primarily probands) and controls drawn from the families. Families with highest density of alcohol dependence and/or extreme event-related oscillation data [phs000763]. GWAS data on 119 extended families of European descent are available here, along with extensive documentation. Study on the Genetics of Alcoholism (COGA): African American Family GWAS [phs000976]. GWAS data on all available COGA families of African descent are available. COGA: Smokescreen GWAS [phs001208]. GWAS data on all remaining COGA DNA samples, primarily of other racial background, were genotyped on the Smoke Screen array. A listing of all sequenced pairs is provided in the documentation to facilitate the merging of these samples.

  Study phs000763

• NHLBI TOPMed: Genomic Activities such as Whole Genome Sequencing and Related Phenotypes in the Framingham Heart Study

  The Framingham Heart Study (FHS) is a prospective cohort study of 3 generations of subjects who have been followed up to 65 years to evaluate risk factors for cardiovascular disease. Its large sample of ~15,000 men and women who have been extensively phenotyped with repeated examinations make it ideal for the study of genetic associations with cardiovascular disease risk factors and outcomes. DNA samples have been collected and immortalized since the mid-1990s and are available on ~8000 study participants in 1037 families. These samples have been used for collection of GWAS array data and exome chip data in nearly all with DNA samples, and for targeted sequencing, deep exome sequencing and light coverage whole genome sequencing in limited numbers. Additionally, mRNA and miRNA expression data, DNA methylation data, metabolomics and other 'omics data are available on a sizable portion of study participants. This project will focus on deep whole genome sequencing (mean 30X coverage) in ~4100 participants and imputed to all with GWAS array data to more fully understand the genetic contributions to cardiovascular, lung, blood and sleep disorders. Also available are aptamer proteomic profiling, RNAseq and 850K array DNA methylation data that predominantly overlap with participants with WGS data. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs000007.

  Study phs000974

• NHLBI TOPMed: Genetic Epidemiology Network of Salt Sensitivity (GenSalt)

  The GenSalt study aims to identify genes which interact with dietary sodium and potassium intake to influence blood pressure in Han Chinese participants from rural north China. Whole genome sequencing will be conducted among 1,860 participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study. We will work in collaboration with participating TOPMed studies to identify novel common, low-frequency and rare variants associated with an array of cardiometabolic phenotypes. In addition, we will explore the relation of low-frequency and rare variants with salt-sensitivity among GenSalt study participants.

  Study phs001217

• Ecological Stressors, PTSD, and Drug Use in Detroit: The Detroit Neighborhood Health Study (DNHS)

  The Detroit Neighborhood Health Study (DNHS) is a prospective, representative longitudinal cohort study of predominantly African American adults living in Detroit, Michigan. The overall goal of the DNHS is to identify how genetic variation, lifetime experience of stressful and traumatic events, and features of the neighborhood environment predict psychopathology and behavior. Cohort participants were selected with a dual-frame probability design, using telephone numbers obtained from the U.S. Postal Service Delivery Sequence Files as well as a listed-assisted random-digit-dial frame. Individuals without listed landlines or telephones and individuals with only a cell phone listed were invited to participate through a postal mail effort. Participants completed a 40 minute, structured telephone interview annually between 2008-2012 to assess perceptions of participants' neighborhoods, mental and physical health status, social support, exposure to traumatic events, and alcohol and tobacco use; each participant was compensated $25USD. All survey participants were offered the opportunity to provide a specimen (venipuncture, blood spot, or saliva) for immune and inflammatory marker testing as well as genetic testing of DNA. Participants received an additional $25USD if they elected to give a sample. Informed consent was obtained at the beginning of each interview and again at specimen collection. The Institutional Review Board of the University of Michigan reviewed and approved the study protocol. The DNHS submission to dbGaP includes phenotype data from all five survey waves (n=1039), all available GWAS data for participants who completed wave 4 (n=507), methylation data for wave 1, wave 2, wave 4, and wave 5 participants (n = 561), and RNA sequencing (n=145) and small RNA sequencing data for wave 2 and wave 4 participants (n = 483).

  Study phs000560

• Gene Variants in Pheochromocytoma and Paraganglioma

  Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla and in extra-adrenal locations, respectively. PPGL has the strongest hereditary risk of all endocrine neoplasms with about 40% of cases harboring germline mutations and another 25-30% of cases arising from somatic mutations. To date, over 20 susceptibility genes have been suggested to play a role in PPGL pathogenesis, with more genes still being researched. This project will seek to identify new candidate genes in apparently sporadic PPGLs to reveal a possible genetic background in cases without variants in known susceptibility genes. Knowledge of the genetic background and the genes involved in the pathogenesis of PPGL allows for clustering and/or development of targeted therapies for the tumors that cannot be surgically resected or tumors that have metastasized.

  Study phs002405

• Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

  The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The specific aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) Collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) Collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.

  Study phs001591

• Study on the Genetics of Alcoholism (COGA): Smoke Screen and Exome Sequencing

  This is a family study of alcoholism, in which the subjects have been drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), a large, ongoing family-based study that includes subjects from seven sites around the US. COGA has gathered detailed, standardized data on study participants, including diagnostic and neurophysiological assessments. This project has already proved successful in identifying several genes that influence the risk for alcoholism and neurophysiological endophenotypes, which have been independently replicated. COGA data were included as part of two Genetic Analysis Workshops, and the phenotypes are familiar to the genetics community. Alcoholic probands were recruited from treatment facilities, assessed by personal interview, and after securing permission, other family members were also assessed. A set of comparison families was drawn from the same communities as the families recruited through an alcoholic proband. Assessment involved a detailed personal interview developed for this project, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), which gathers detailed information on alcoholism related symptoms along with other drugs and psychiatric symptoms. Many participants also came to the laboratories for electroencephalographic studies. Neurophysiological features that have been shown to be useful endophenotypes for which we have linkage and in some cases association results are included on a subset of the case-control sample: the beta power of the resting electroencephalogram (EEG), the P3(00) amplitude of the visual event-related potential (ERP), and the theta and delta event-related oscillations (EROs) underlying the P3.

  Study phs001208

• NHLBI TOPMed: Genomic Summary Results for the Trans-Omics for Precision Medicine Program

  The NHLBI Trans-Omics for Precision Medicine (TOPMed) program aims to identify the genetic basis of variation in biomedical phenotypes, with emphasis on those related to heart, lung, blood and sleep disorders, as part of a broader Precision Medicine Initiative. The TOPMed program has provided whole genome sequencing (WGS) to over 80 different studies that had previously recruited participants and collected extensive phenotype data. Many TOPMed investigators affiliated with these studies have organized their activities into phenotype-focused Working Groups and have developed genotype-phenotype association projects. These analyses have resulted in valuable cross-study Genomic Summary Results (GSR) that include whole genome association test results of both common and rare variants. Most of the analyses include data from multiple studies, some of which are based on sensitive populations, precluding public sharing of GSR. This dbGaP accession provides a mechanism for sharing sensitive GSR, using the controlled-access mechanisms of dbGaP to provide protections for sensitive populations.

  Study phs001974

• Multi-Ethnic Study of Atherosclerosis (BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Available Data Data available for request include data from exam 1 through exam 6 and events data updated through calendar year 2020. Also included are data from twenty ancillary studies: #079 (NT-ProBNP and Troponin), #042 (Epidemiology of Vascular Inflammation and Atherosclerosis), #081 (Apolipoproteins B and A-1), #067 (MRI RV-Function), #057 (Cystatin-C), #244 (NT Pro-BNP and HS Cardiac Troponin-T), #205 (Brachial IMT), #113 (Exam 5 Sleep), #047/075 (Vitamin D), #195 (Fatty Acid), #200 (Total FFA), #324 (Lipoprotein A), #023 (Neighborhood Racial Segregation), #118 (Stress Cortisol), #002 (Aortic Valvular Calcium), #085 (NAFLD Liver CT), #029 (Exams 3 and 4 Cortisol), #039 (Air Pollution), #077 (Fetuin-A), and #349 (Atrial Hemodynamics).The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent.Data available for request include phenotypic data previously released on BioLINCC. Raw images (e.g., Echocardiograms) are available through accession phs003702 and raw tracing data files (e.g. Electrocardiogram). are available through accession phs003703. These new data are intended to be made available to interested researchers via BioData Catalyst, and will include participants irrespective of participation in genetics (i.e. the full MESA cohort, phs000209), and may be merged with currently posted (to dbGaP) phenotype and molecular datasets (WGS, GWA, RNA Seq, Methylation, Metabolomics, and Proteomics).

  Study phs003288

• Kids First and INCLUDE: Down Syndrome, Heart Defects, and Acute Lymphoblastic Leukemia

  This project is a collaboration with the trans-NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, which seeks to improve health and quality-of-life for individuals with Down syndrome, and NHLBI's TransOmics for Precision Medicine (TOPMed) program, which seeks to apply omics technologies to improve scientific understanding of the fundamental biological processes that underlie heart, lung, blood, and sleep (HLBS) disorders. The data is also available at the INCLUDE Data Hub.Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital heart disease (CHD) and acute leukemia. For instance, children with DS have a 2000-fold increased risk of atrioventricular septal defects (AVSD) and a 20-fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both of these phenotypes, however, the genomic architecture of risk remains largely undiscovered. In this joint Kids First/TOPMed/INCLUDE project, we are currently including >2,000 samples for whole-genome sequencing, including: 1) paired germline-tumor samples from children with DS-ALL; and 2) samples from families with DS-CHD. This work will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer.The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Therefore, the aims of our study are: 1) compare whole-genome sequencing (WGS) data between children with documented DS-AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development; and 2) compare WGS data between children with documented DS-ALL and children (from Aim 1) with DS who do not have a known history of ALL. We will also examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-AVSD and DS-ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer.Additional Pediatric Cardiac Genetics Consortium (PCGC) data from children affected with Down syndrome and congenital heart disease are accessible through two separate dbGaP studies: phs001138 (Kids First) and phs001194 (TOPMed).

  Study phs002330

• NHLBI TOPMed: My Life Our Future (MLOF) Research Repository of Patients with Hemophilia A (Factor VIII Deficiency) or Hemophilia B (Factor IX Deficiency)

  Hemophilia A and B are X-linked bleeding disorders resulting from a deficiency in coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Hemophilia affects approximately 1/5000 male births worldwide, and results in premature death and disability due to bleeding if coagulation factor replacement therapy is not used effectively. Hemophilia is clinically categorized by coagulation factor activity levels and ranges in severity from mild (6% to 30%) to moderate (1-5%) to severe ( The My Life Our Future (MLOF) project (www.mylifeourfuture.org) is a national resource developed by a partnership of BloodworksNW (BWNW, formerly the Puget Sound Blood Center), the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF) and Bioverativ, to provide free F8 and F9 gene variant analysis to patients with hemophilia A or B, and to establish a research repository of DNA sequence, DNA, RNA, buffy coat, serum and plasma. The sequence analysis and serum samples are linked to a phenotypic database hosted by ATHN, with samples submitted and clinical data entered at ~100 hemophilia treatment centers (HTCs) nationwide. (See ATHN Research Report Brief in the resource center at www.athn.org). MLOF has become the largest hemophilia genetic project worldwide. The roles of the MLOF partners are: BWNW, to serve as the central laboratory for the project and house the research repository; ATHN, to support and provide the administrative link with HTCs, to facilitate the collection of accurate phenotypic data, to conduct research review and approval for use of the repository and with BWNW to provide samples and data for research projects; NHF, to provide consumer education and facilitate consumer input into the project; and Bioverativ, to provide financial support and scientific input. The project is governed by a Steering Committee consisting of one representative from each organization. Subject samples chosen from the MLOF parent study for TOPMed and WGS were drawn from those who gave (or parents gave) informed consent for the Research Repository and included patients of all severities and type, but with an emphasis on those with severe hemophilia and others at increased risk of neutralizing antibody (inhibitor) formation and who had samples in the Research Repository (plasma, serum, RNA) for potential additional -omic studies. Also included were samples from subjects where a likely causative variant for hemophilia was not found in the F8 or F9 coding region, intron-exon boundaries or immediate upstream and downstream regions. Since hemophilia is an X-linked disorder, the majority of subjects are male. Racial distribution is similar to the overall population distribution.

  Study phs001515

• Genetic Susceptibility and Biomarkers of Platinum-Related Toxicities

  The Platinum Study is an R01-funded, multicenter study of testicular cancer survivors that characterizes both long-term cisplatin-induced peripheral neuropathy (CisIPN) and cisplatin-associated ototoxicity, i.e., permanent, bilateral hearing loss. We collected data abstracted from medical records (e.g., cumulative cisplatin dose), conducted audiometric examinations, and administered self-report questionnaires, which included CisIPN symptoms.

  Study phs001621

• Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET)

  STARNET is a genetics of RNA expression study of multiple disease-relevant tissues obtained from living patients with cardiovascular disease. Tissue samples are obtained from blood, atherosclerotic-lesion-free internal mammary artery (MAM) and atherosclerotic aortic root (AOR), subcutaneous fat (SF), visceral abdominal fat (VAF), skeletal muscle (SKLM), and liver (LIV) during open thorax surgery of 600 coronary artery disease (CAD) patients. All patients gave written informed consent. The inclusion criterion was eligibility for coronary artery by-pass graft (CABG) surgery. Patients with other severe systemic diseases, such as active systemic inflammatory disease or cancer, were excluded. The primary clinical end points were the SYNTAX score based on the extent of coronary atherosclerosis assessed from preoperative angiograms. The STARNET patients are Caucasians (31% females); 32% had diabetes, 75% had hypertension, and 67% had hyperlipidemia; and 33% had an MI before age 60. By New York Heart Association criteria, 45% were class I, 42% class II, 9% class III, and 1% class IV. TYPES AND RNA SEQUENCING: 566 DNA genotype and 3577 RNA-seq profiles from seven tissues from 600 STARNET CABG patients passed quality control (on average 511 RNA-seq profiles/tissue). DNA was genotyped with the OmniExpress Exome array (Illumina, ~900k SNPs) and imputed to a total of 14,098,063 DNA variant calls (6,245,505 with minor allele frequency >5%). The STARNET subjects mainly overlap with Caucasian of Northern European (Finnish) descent. RNA sequencing was performed using the HighSeq2000 platform, poly-A (LIV, SKLM, VAF, SF and blood) and ribo-zero (AOR, MAM) protocols with 50-100 bp read lengths, single end to 15-30 million read depth.

  Study phs001203

• CIDR: NINDS High Throughput Genotyping Resource Access for Structural Hindbrain Disorders

  Recessive forms for many structural brain disorders (SBDs), including cerebellar hypoplasia (CBH), corpus callosum hypoplasia (CCH), cobblestone lissencephaly (COB), classical lissencephaly (LIS), microcephaly (MIC), and pontocerebellar hypoplasia (PCH), have been described. Patients usually present to the clinic with neurodevelopmental disorders (NDDs), including autism, epilepsy, intellectual disability, and cerebral palsy. Subsequent brain MRI usually leads to the diagnosis of an SBD. While a handful of genes that cause these diseases have been identified, most patients do not have mutations in these genes, suggesting that there is still much work to be done in identifying the genetic causes of these disorders. We have recruited a cohort of families with inherited SBDs, most from families with documented parental consanguinity with more than one affected member. Current approaches utilizing exome sequencing of SBD affected members still leave most cases unsolved, in part because there are too many possible variants to consider. Linkage analysis and Whole Genome Sequencing (WGS) will allow us to extract all the useful genetic information from the family, taking advantage of each genetically informative meiosis in each family. We propose to analyze up to 100 SBD families for 500 samples per year for 4 years, through the CIDR SNP Genotyping Service, in parallel with already-funded exome sequencing of affects, leveraging off an already funded Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) effort to identify new causes of SBDs. Understanding the pathogenetic mechanisms underlying recessive pediatric SBDs will lead to better diagnostic and therapeutic opportunities for patients, and may shed light on complex NDDs. Ultimately, this work will identify new genetic disease loci to provide insight into pediatric SBD, with the hope to mitigate the impact of SBD worldwide.Public Health Significance: NDDs affect approximately 4-­6% of the general population, most notably children, and are evident in disorders, such as intellectual disability, epilepsy, and autism, with estimated yearly costs of $51.2B for intellectual disability, $11.5B for cerebral palsy, and $2.5B for visual impairment, making up >5% of total health care costs. Recessive NDDs impose enormous personal, social, and economic costs because of the early onset and the lifetime of medical dependence that often ensues. Genetic testing is critical to the diagnosis and treatment of these diseases. Many of the diseases under study have no treatment or cure. Structural brain diseases (SBDs) underlie a large percentage of these diseases, and are defined loosely as any condition in which defects in the structure or volume of a key brain component. SBDs are divided into major categories based upon the anatomical brain location. The major types involve the anatomical structures of the developing neural tube, forebrain, hindbrain, cerebral cortex, and those affecting overall brain size. For the purposes of this application, we have excluded SBDs resulting from environmental causes (i.e. prematurity-­induced), those below the brainstem, or those unlikely to be due to a germline or de novo mutation (i.e. focal SBDs or simplex disease).

  Study phs002621

• NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

  This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

  Study phs000988

• NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure = 140 mm Hg or diastolic blood pressure = 90 mm Hg based on the second and third readings at the time of their clinic visit. Only participants of the African-American Cohort were sequenced through TOPMed. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals. Comprehensive phenotypic data for GENOA study participants are available through dbGaP phs001238.

  Study phs001345

• DEMENTIA-SEQ: WGS in Lewy Body Dementia and Frontotemporal Dementia

  Lewy body dementia, amyotrophic lateral sclerosis/frontotemporal dementia, and multiple system atrophy are age-related, neurodegenerative syndromes that are poorly understood. Delineating the genetic risk that is driving the pathophysiology of these neurological diseases is fundamental for understanding disease mechanisms and for developing disease-modifying treatments. In version 1 of the study/dbGaP deposition, we performed a whole-genome sequencing study consisting of 7,403 total samples, including 2,633 genomes from patients with Lewy body dementia, 2,641 frontotemporal dementia patients, and 1,980 neurologically healthy controls. Of these, 6,907 were uploaded to dbGaP as the basis of the DementiaSeq, phs001963 dataset. The data relating to these samples are available on dbGaP. In version 2 of this study/dbGaP deposition, we made much of these data available on Anvil. More specifically, data for 6,254 of these samples were also uploaded to the ALS Compute platform on AnVIL. The data for the remaining 653 samples are only available on dbGaP. The dbGaP/AnVIL Table lists the availability of dbGaP and AnVIL for each individual sample: phd008475.In version 3 of the study/dbGaP deposition, we added whole-genome sequence data generated using DNA samples obtained from 683 patients diagnosed with multiple system atrophy.

  Study phs001963

• Brain Cell Type-Specific Enhancer-Promoter Connectivity Maps and Disease Risk Association

  These studies map the epigenetic landscape of microglia, neurons, astrocytes and oligodendrocytes. The initial study compared acutely isolated microglia to cultured microglia from the same donors, to identify changes that occur when microglia are removed from the brain microenvironment. In collaboration with the Rady Children's Hospital, we obtained brain tissue samples from pediatric patients representing putative normal tissue resected to gain access to brain tumors as well as tissue resected to remove epileptic foci. We assayed microglia isolated from these samples using RNA-seq, ATAC-seq and ChIP-seq for PU.1, H3K4me2, and H3K27ac. For patients from whom a sufficient cell number was obtained, we additionally cultured their microglia for up to 7 days and subjected these to the same suite of assays. In a follow-up study, we obtained brain tissue from a comparable cohort of pediatric epilepsy patients from Rady Children's Hospital. We isolated nuclei from microglia, neurons, astrocytes and oligodendrocytes, and assayed for ATAC-seq, ChIP-seq for H3K4me3, and H3K27ac, and PLAC-seq (Proximity Ligated ChIP-seq). We isolated microglia from human fetal and postnatal sample and assayed for bulk RNA-seq, bulk ATAC-seq, bulk H3K27ac ChIP-seq, single-cell RNA-seq (scRNA-seq) and single-cell ATAC-seq. For these studies, human microglia are defined by signature genes/proteins, such as P2RY12, SALL1, and CX3CR1.

  Study phs001373

• Genomic Profiling of Melanoma

  This study reports on genomic profiling [whole-exome sequencing (WXS), bulk RNA sequencing (RNA-seq), and/or single-cell RNA sequencing (scRNA-seq)] of patient-derived melanoma samples and matched normal samples. The goal is to elucidate the genetic and cellular basis of sun-exposed and sun-shielded melanomas and to relate these findings to survival and regional metastasis. Specimens were collected by the Tissue Resource Core of the Yale SPORE in Skin Cancer with participants' informed signed consent according to Health Insurance Portability and Accountability Act (HIPAA) regulations with a Human Investigative Committee protocol. The melanomas used for sequencing were from fresh or snap-frozen tumors, or from short-term cell cultures. The cell cultures were routinely checked for mycoplasma contamination and were discarded when found positive. Matching normal DNA was from circulating lymphocytes or normal skin. We also include 77 WES-sequenced samples from the Yale Spitzoid neoplasm repository, which collects specimen and data according to a protocol approved by the Yale Human Investigative Committee.

  Study phs000933