3613 results for "*geneti*"

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• Mapping Disease Pathways for Biliary Atresia

  Biliary atresia (BA) is a poorly understood rare disease that causes jaundice and liver failure at birth due to underdeveloped bile ducts. Associated defects include poor development of the portal vein and involvement of non-hepatic organs. After initial surgical drainage in all patients, the majority need liver transplantation because of progressive cirrhosis. In addition to the risks of lifelong immunosuppression after liver transplantation, the post-transplant biliary atresia patient can experience surgical complications like portal vein thrombosis along with the consequences of extrahepatic involvement often found in affected patients. To determine the genetic basis of this disease, a genome-wide association study of 811 BA cases, all of whom received liver transplantation, and 4654 controls was performed with a 2.5 million SNP array. The study found that BA associates with polygenic risk conferred by over 6000 common variants, minor allele frequencies >1%, in 102 ciliogenesis and planar polarity effector genes (CPLANE). Whole genome sequencing of 100 of 811 cases revealed that most cases harbored rare variants, allele frequencies Whole genome genotyping, gene expression and whole genome sequencing data is being made available.

  Study phs003458

• Acute Respiratory Distress Network (ARDSNet) Studies 10 and 12 Statins for Acutely Injured Lungs from Sepsis (SAILS) (ARDSNet-SAILS-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-SAILS include Plasma, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The SAILS trial was intended to assess the efficacy and safety of oral rosuvastatin in participants with sepsis-induced Acute Lung Injury (ALI) and test the hypothesis that rosuvastatin therapy would improve the clinical outcomes of critically ill participants with sepsis-associated acute respiratory distress syndrome (ARDS). Background In ARDS, inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in participants with sepsis. Participants There were 745 participants. Design Participants were randomly assigned in permuted blocks to receive either enteral rosuvastatin or placebo. A 40 mg loading dose of the study drug was administered within four hours after randomization. Subsequently, maintenance doses of 20 mg were administered daily until the third day after discharge from the intensive care unit, study day 28, hospital discharge, or death, whichever came first. The primary outcome measure was mortality before hospital discharge home or until study day 60 if the participant was still in a health care facility. Secondary outcome measures included the number of ventilator-free days to day 28, organ-failure-free days to day 14, and ICU-free days to day 28. Conclusions The study was stopped because of futility after 745 of an estimated 1000 participants had been enrolled. There was no significant difference between study groups in 60 day in-hospital mortality or in mean ventilator-free days. The rosuvastatin group had fewer days free of hepatic or renal failure. Thus, rosuvastatin therapy did not improve clinical outcomes in participants with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction.

  Study phs003736

• Whole Genome Sequencing of DS1-IPS4 Down Syndrome iPSC Clone

  This study was designed to sequence the variants from our parental Down syndrome iPS line, created from fibroblasts available from Coriell. This was done to allow us to 1) better identify target sites for transgene insertion and 2) identify variants that were heterozygous on the three copies of chromosome 21.

  Study phs004097

• Childhood Cancer Data Initiative (CCDI): Enhancement of Data Sharing in Pediatric, Adolescent and Young Adult Cancers

  NCI's Childhood Cancer Data Initiative (CCDI) is building a community centered around childhood cancer care and research data. Through enhanced data sharing, we can improve our understanding of cancer biology to improve preventive measures, treatment, quality of life, and survivorship, as well as ensure that researchers learn from every child with cancer. While childhood cancers represent the leading cause of death in children over the age of 1, they are collectively rare, comprising approximately 1%‒3% of cancers diagnosed annually in the United States. Information on diagnosis, treatment, and outcomes is often stored at the hospital or institution where a child is treated, making it difficult to answer scientific questions about childhood cancer. Sharing clinical care and research data generated by children's hospitals, clinics, or networks broadly with the community can help us learn faster and, on a scale much larger than any single institution caring for children can learn on its own. To exploit the rapid advances in high-throughput DNA sequencing technologies and realize the goals of precision cancer medicine, the UMICH Cancer Center established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). This UMICH Cancer Center provisions genomic data derived from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) clinical sequencing assay for patients that fall within the inclusion criteria of the CCDI data sharing initiative. An "integrative sequencing approach" carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. Using a number of computational pipelines that we have developed in-house or have adapted from the public domain, candidate molecular aberrations are nominated and then analyzed by scientists for clinical significance and/or relevance. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant.

  Study phs002431

• GENomics of CAncer DisparitiEs (GENCADE)

  Genetic ancestry-concordant RNA splicing events in men with prostate cancer (PCa) involve cancer promoting genes and associate with disease recurrence after radical prostatectomy. Patients diagnosed with PCa who were scheduled to undergo radical prostatectomy or biopsy were enrolled in the GENCADE study, according to the Institutional Review Board (IRB)-approved protocol Pro00053535 (NCT02229565). With respect to NCT02229565, the descriptors “African American” and “Caucasian American” refer to the same patients described as “Black” and “White”, respectively, herein. Patients were also co-enrolled to the Duke BioRepository & Precision Pathology Center (BRPC) protocol (Pro00035974) to facilitate tissue collection.

  Study phs003731

• Neurogenetic Studies of Trichotillomania and Excoriation Disorder

  The overall objective of this study is to use a series of state-of-the-art neurogenetic approaches to advance our understanding of the genes and pathways that contribute to trichotillomania and excoriation disorder. In aim 1, we will use whole-exome DNA sequencing to examine rare sequence variants in 200 parent-child trios where the child has trichotillomania or excoriation disorder. In aim 2, we will examine rare copy number variants in the same 200 parent-child trios using genome-wide array data or low-pass whole-genome DNA sequencing. In aim 3, induced-pluripotent stem cell brain organoids will be derived from 4 cases with trichotillomania and/or excoriation disorder and matched controls. Single-cell RNA sequencing (scRNA-seq) will be performed to explore transcriptomic differences between cases and controls. Genomic data generated under this award will be shared through dbGaP.

  Study phs004005

• FORCE Trial: Resistance Training Intervention Among Colon Cancer Patients

  Our study population was composed of participants of the FORCE clinical trial, which was a randomized resistance training intervention study for Stage II and III colon cancer patients undergoing chemotherapy. Patients were recruited from Kaiser Permanente of Northern California, the Penn State Cancer Institute, and the Dana Farber Cancer Institute and were assigned to resistance training or usual care within the first weeks of adjuvant chemotherapy. Lean mass was evaluated at the beginning and the end of the study, and participants were monitored for toxicities associated with chemotherapy and chemotherapy dose modifications. Genome-wide DNA methylation was assayed using peripheral blood collected at the FORCE trial baseline and the post-intervention visit using the Infinium MethylationEPIC v1.0 (EPIC) BeadChips (Illumina). EPIC array signal intensities were preprocessed and used to estimate site-specific DNA methylation levels, which were used for the estimation of several epigenetic clocks. Our study hypothesized that those with accelerated epigenetic age at the beginning of chemotherapy would be more likely to have modifications to their assigned chemotherapy regimen driven by a higher burden of chemotoxicities. We also hypothesized that epigenetic age acceleration would significantly increase over the course of chemotherapy and that a resistance training intervention would reduce the rate of change.

  Study phs003671

• NCTN: Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System with Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation (ACNS0333)

  Study ID: ACNS0333NCT Number: NCT00653068 Children's Oncology Group (COG)Submitted in collaboration with the NCTN/NCORP Data ArchiveTrial Title: NCTN: Treatment of Atypical Teratoid/Rhabdoid Tumors (AT/RT) of the Central Nervous System with Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation (ACNS0333)Trial Description: This phase III trial studies the side effects of combination chemotherapy, 3-dimensional conformal radiation therapy, and an autologous peripheral blood stem cell transplant, and to see how well they work in treating young patients with atypical teratoid/rhabdoid tumor of the central nervous system. Giving high-dose chemotherapy before an autologous peripheral blood stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy or radiation therapy. Clinical data presented in the following publication(s): PMID 32105509 Disease type(s): CNS Neoplasm (Primary Tumor) - Embryonal Tumors of the CNSClinical Dataset(s) included:NCT00653068-D1 (PMID 32105509): There are 3 datasets (-D1 through -D3) for ACNS0333's primary publication, PMID 32105509. This dataset, NCT00653068-D1, provides information on the flow of patients enrolled in ACNS0333 through therapy shown in the CONSORT diagram in Figure 2, baseline characteristics, extent of tumor resection, methylation, ATRT subgroup, SMARCB1 status, induction response, survival, and cause of death data. There is one row for each patient enrolled.NCT00653068-D2 (PMID 32105509): There are 3 datasets (-D1 through -D3) for ACNS0333's primary publication, PMID 32105509. This dataset, NCT00653068-D2, provides specific incidence of grade 4 or higher adverse events that occurred in 5% or more of patients in at least one phase of therapy, as presented in Table A2 (Treatment-Associated Toxicity).NCT00653068-D3 (PMID 32105509): There are 3 datasets (-D1 through -D3) for ACNS0333's primary publication, PMID 32105509. This dataset, NCT00653068-D3, provides event-free survival (EFS) data for the primary analytic comparison: ACNS0333 patients 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 phs004137

• Comprehensive Single-Cell Multiomic Profiling of the Human Heart in Health and Disease

  We profiled all four chambers (left ventricle, right ventricle, left atrium, right atrium) of human hearts from 36 donors (23 with heart failure, 13 non-failing controls) using single-cell multiome (joint chromatin accessibility and gene expression), Droplet Paired-Tag (joint histone modification H3K27ac/H3K27me3 and gene expression), and Droplet Hi-C (single-cell chromatin conformation) assays. The heart failure cohort included 13 ischemic (ICM) and 10 non-ischemic cardiomyopathy (NICM) patients. Genotyping array and whole genome sequencing (WGS) data were also generated from the same donors (when applicable - not all donors have WGS/Genotyping data). Integrative analyses across 759,222 total nuclei revealed cell type-specific changes in gene regulatory programs, chromatin organization, and transcription factor networks - particularly in cardiomyocytes and fibroblasts - during heart failure. Mapping cell type-specific enhancer-gene interactions enabled identification of likely causal genetic contributors to heart failure from GWAS data. Data include individual-level genotype, phenotype, WGS, single-cell RNA-seq (scRNA-seq), single-cell ATAC-seq (scATAC-seq), single-cell histone modification, and single-cell Hi-C data (scHi-C).

  Study phs004650

• MP2PRT: Genomic and Molecular Characterization of Biomarkers Associated with Tumor Angiogenesis, DNA Repair, and Immunologic Tolerance using Samples from the NRG Oncology Phase 3 Randomized Trial, GOG-0240 (NCT00803062)

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study is one of the selected studies under this program. For this study, genomic characterization (WGS, WXS, Total RNAseq, miRNAseq) has been performed on cervical tumor tissue from patients with advanced disease (persistent, recurrent, and metastatic) and matching germline samples. It is hypothesized that the characterization of these tissues using next generation sequencing will lead to the identification of relevant novel genetic aberrations within the immunologic, DNA repair, and tumor angiogenesis domains that dichotomize the study population into exceptional responders and non-responders to systemic therapy, with a spectrum of response manifesting between the two extremes.

  Study phs002293

• Clarification of Optimal Anticoagulation through Genetics (COAG) (COAG-BioLINCC)

  Objectives: The COAG trial tested whether genotype-guided dosing of warfarin improves anticoagulation control during the first 4 weeks of therapy when compared to clinical-guided dosing.Background: Warfarin is highly efficacious at preventing thromboembolism, a condition associated with substantial morbidity and mortality. Individuals taking warfarin require dosage adjustments to maintain a therapeutic international normalized ratio (INR), particularly at the beginning of therapy. Out of range INR can increase risk of thromboembolism, bleeding, and early discontinuation of a highly useful therapy. Genotype-guided dosing of warfarin may be a more effective way of dosing warfarin when compared to only using clinical information. Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. Prior to the COAG trial, the effectiveness of genotype-guided dosing of warfarin had been limited to small clinical trials or observational studies, with equivocal results. Therefore comparison of the two strategies was needed to determine if use of genetic information is more effective in warfarin dosing than using clinical information.Participants: Participants were adults initiating warfarin therapy with a target international normalized ratio (INR) of 2 to 3 and an expected duration of therapy of at least 1 month. Exclusion criteria included current warfarin use, prior warfarin therapy with a known stable dose, and abnormal baseline INR (off warfarin). A total of 1015 subjects were enrolled in the study.Design: The COAG study was a multicenter, double-blind, randomized trial that compared two approaches to guiding warfarin therapy initiation. Subjects were randomly assigned in a 1:1 ratio to a dosing strategy during the first 5 days of warfarin therapy. For each dosing strategy, a dose-initiation algorithm was used during the first 3 days of therapy, and a dose-revision algorithm was used on day 4, 5, or both. The algorithms for the genotype-guided dosing strategy included clinical variables and genotype data for CYP2C92, CYP2C93, and VKORC1. The algorithms for the clinically based dosing strategy included clinical variables only. If genotype information was not available for a patient in the genotype-guided dosing group before the administration of warfarin on any given day in the first 5 days, the clinical algorithm was used on that day.During the first 4 weeks of therapy, patients and clinicians were unaware of the actual dose of warfarin that was administered. After the 5-day initiation period, dosage was adjusted during the first 4 weeks using standardized dose-adjustment techniques, starting with the doses predicted by the algorithms and making the same relative adjustments on the basis of the INR in the two study groups. Clinicians were informed of the relative dose change at each INR measurement but not the actual dose of warfarin. Subjects were to be followed for a total of 6 months. The primary outcome was the percentage of time that the subject's INR was in the therapeutic range (2 to 3) from the completion of the intervention period (day 4 or 5) through day 28 of therapy. Secondary outcomes included a composite outcome of any INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks. Conclusions: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

  Study phs004634

• The Genomic and Transcriptomic Landscape of a HeLa Cell Line

  HeLa is the most widely used model cell line for studying human cellular and molecular biology. To date, no genomic reference for this cell line has been released, and experiments have relied on the human reference genome. Effective design and interpretation of molecular genetic studies performed using HeLa cells require accurate genomic information. Here we present a detailed genomic and transcriptomic characterization of a HeLa cell line. We performed DNA and RNA sequencing of a HeLa Kyoto cell line and analyzed its mutational portfolio and gene expression profile. Segmentation of the genome according to copy number revealed a remarkably high level of aneuploidy and numerous large structural variants at unprecedented resolution. Some of the extensive genomic rearrangements are indicative of catastrophic chromosome shattering, known as chromothripsis. Our analysis of the HeLa gene expression profile revealed that several pathways, including cell cycle and DNA repair, exhibit significantly different expression patterns from those in normal human tissues. Our results provide the first detailed account of genomic variants in the HeLa genome, yielding insight into their impact on gene expression and cellular function as well as their origins. This study underscores the importance of accounting for the strikingly aberrant characteristics of HeLa cells when designing and interpreting experiments, and has implications for the use of HeLa as a model of human biology. Copyright Landry et al., "The Genomic and Transcriptomic Landscape of a HeLa Cell Line," G3: Genes | Genomes | Genetics (2013).

  Study phs000643

• The Study of Soy Isoflavones in Asthma (SOYA-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.ObjectivesTo determine whether participants with poorly controlled asthma have improved asthma control and lung capacity when prescribed a soy isoflavone supplement versus a placebo.BackgroundThe prevalence of asthma is determined by multiple environmental and genetic factors, and over the last several decades, both the prevalence and severity of asthma have increased. Specific causes remain unknown, but diet is one of the environmental factors associated with increased prevalence and severity.Previous studies had shown that those who consume soy isoflavones have better lung function compared to those who do not. The study focused on two particular iosflavones, genistein and daidzein, based on the strong preclinical and epidemiological data that supported the prediction of beneficial dietary effects for asthma patients. At the cellular level, genistein exerts antioxidant effects that are equal to or greater than those of vitamin C. Prior to the clinical trial, recent in vitro results showed that genistein inhibits synthesis of human peripheral blood eosinophil cysteinyl leukotrienes via inhibition of 5-lipoxygenase. Synthesis of the eosinophil cysteinyl leukotrienes is a key pathways that may contribute to asthma severity.ParticipantsEligible participants were over the age of 12, of either gender, and were non-smokers for 6 months or longer with a less than 10 pack-year smoking history. The SOYA trial had 193 participants randomized into the placebo and soy isoflavone arms for a total of 386 participants. 179 participants in the placebo arm and 166 participants in the soy isoflavone arm completed the trial, which was defined as having an FEV1 measurement at 24 weeks.Participants were included if they had been diagnosed by a physician with asthma, were currently prescribed daily controller asthma medication, or had a FEV1 equal or greater than 50% predicted pre-bronchodilator and/or at least 12% increase in FEV1 15-3 minutes after inhaling 2-4 puffs of albuterol or positive methacholine challenge (20% fall in FEV1 at less than 8 mg/mL) with either parameter available from the previous two years. Participants with poor asthma control were included if they met at least one of the following: a score of 1.5 or greater on the Juniper Asthma Control Questionnaire, use of beta-agonist for asthma symptoms two or more times per week, nocturnal awakening with asthma symptoms more than once per week, and/or two or more episodes of asthma symptoms in the past 12 months with each requiring at least one of the following: emergency department visit, unscheduled physician visit, prednisone course, and/or hospitalization.Participants were excluded from the trial for potential non-adherence or allergy to treatment, not meeting FEV inclusion criteria, use of concurrent and/or prior (DesignSOYA was a phase 4 interventional clinical trial. The study was multicenter, randomized, and double blind. Parallel assignment treatment arms were structured to determine the efficacy of soy supplementation and diet modification on asthma control.The primary outcome measured was the mean change in forced expiratory volume in the first second (FEV1), at the 24 week visit. Secondary outcomes were asthma symptoms, episodes of poor asthma control, Asthma Control Test score, and systemic and airway biomarkers of inflammation.Participants were randomly assigned in a 1:1 allocation ratio to receive either the soy isoflavone supplement or matching placebo twice daily for six months. Participants were instructed to keep daily diaries recording the following: morning peak expiratory flow, medication use, and asthma symptoms. Participants reported taking at least 1 dose of the study treatment on more than 90% of follow-up days. Clinical assessments and procedures were completed every 4 weeks for a total of 24 weeks. The Block Food Frequency Questionnaire and Soy Foods Screener were administered at visits 2 and 9. Data from daily diaries and pill counts were used to evaluate adherence to the treatment protocol. Each participant's overall diet and dietary soy intake were analyzed at baseline and at 24 weeks to assess stability of diet and nutrient intake during the study.ConclusionsParticipants who received the soy isoflavone supplement exhibited an increase in mean plasma genistein levels; however, no clinically significant improvement was observed in the primary end point of FEV1 at 24 weeks post-randomization between participants treated with soy isoflavone supplement and placebo.JAMA. 2015 May 26;313(20):2033-43

  Study phs004683

• Genetics of Antinuclear Antibodies

  Antinuclear antibodies (ANA) are antibodies that react against self-antigens in the cell. While it has been reported that 12 to 20% of the general population have a positive ANA test, the genetics of ANA positivity is unknown. We performed a genome wide-association study for positive ANA tests among individuals without an ANA related autoimmune disease in the Vanderbilt University Medical Center (VUMC) DNA biobank linked to the de-identified electronic health record (EHR) system. The study is funded by the National Institute of Arthritis and Musculoskeletal and Skin diseases (NIAMS) grant R01AR076516.

  Study phs003189

• Multiomic Landscape of Multiple Myeloma Precursor and Relapsed Disease

  Multiple myeloma (MM) is a treatable, though incurable, plasma cell malignancy. The molecular mechanisms driving disease onset and the emergence of drug resistance remain elusive. To better characterize the mutational, transcriptional, and epigenetic alterations that accompany MM disease evolution, we accessed molecular data from MM patients treated at Moffitt Cancer Center, with bone marrow biopsies collected between 2011 and 2023.We performed scMultiome (single-cell, paired RNA/ATAC-Seq, 10x Genomics) on 18 CD138+-selected bone marrow aspirate samples, including: 2 healthy donors, 3 patients with monoclonal gammopathy of undetermined significance (MGUS), 4 with smoldering myeloma (SMM), 3 with newly diagnosed MM (NDMM), 1 with early relapse MM (ERMM, 1 to 3 lines of therapy), and 5 with late relapse MM (LRMM, 4 or more lines of therapy). Our dataset includes a sequential sample: a patient with a premalignant condition ("scMultiome_SMM_4") that progressed to active myeloma ("scMultiome_NDMM_3"). These data allow for the assessment of transcriptional and epigenetic dysregulation at the cellular level. Our findings illustrate the dynamic epigenetic and transcriptional landscapes that accompany MM disease progression.We also conducted CUT&Tag analysis on 4 NDMM and 4 LRMM samples to map histone modifications, specifically H3K27ac, to investigate their role in transcriptional reprogramming observed in advanced stages of MM. This analysis revealed sample heterogeneity in terms of super-enhancer-regulated genes associated with active transcription.This cohort also includes samples from the clinical trial NCT04151667, “Daratumumab-Based Response-Adaptive Therapy for Older Adults With Newly Diagnosed Multiple Myeloma.” We performed scRNAseq (single-cell RNA sequencing, 10x Genomics) on 30 CD138+-selected bone marrow aspirate samples and 31 pre-sort samples featuring bone marrow mononuclear cells of various cell types from 5 healthy donors and 11 patients with newly diagnosed MM (NDMM). Our dataset includes sequential samples for all 11 NDMM patients, both prior to induction therapy (denoted by ‘a') with Daratumumab and Dexamethasone, and at cycle 2 day 22 (C2D22, i.e., 60 days after induction therapy start, denoted by ‘b'). For three NDMM patients, we also have samples at relapse (denoted by ‘c'). These data allow for the assessment of transcriptional dysregulation at the single-cell level in both the tumor and immune-tumor microenvironment, associated with Daratumumab treatment in NDMM patients.In addition to the molecular data, demographic, and phenotypic information for all samples is provided.

  Study phs003892

• Center for Common Disease Genomics (CCDG) - Neuropsychiatric: Introduction of Exome/Genome Sequencing

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs004430

• Genetics of IgA Vasculitis

  IgA vasculitis (IgAV), also known as Henoch-Schönlein purpura (HSP), is the most common form of childhood vasculitis with skin and systemic manifestations. It's characterized by IgA deposition in blood vessel walls in the skin, joints, gastrointestinal tract, and the glomerular mesangium. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for IgAV. The participants of the GIGA-kids cohort were genotyped by Illumina Multi-Ethnic Global Array, consisting of 741 IgAV cases and 2,167 healthy controls of European ancestry. These cohorts were used in the GWAS meta-analysis, as described in the manuscript entitled "Genome-wide studies define new genetic mechanisms of IgA vasculitis" (Nature Communications 2026, under review).

  Study phs004179

• Genetics of Eating Disorders

  This genetic study examines Anorexia Nervosa, Bulimia Nervosa, and Binge Eating Disorder. We performed whole exome sequencing (WES) on 93 unrelated individuals with eating disorders (38 restricted-eating, 55 binge-eating) to identify novel damaging variants. Using an unbiased, data-driven approach, we prioritized candidate genes with an excessive burden of predicted damaging variants. We then empirically tested one top candidate pathway in a mouse model of binge-like eating. We identified an excess of novel damaging variants in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. The list of genes significantly enriched (OR = 4.6, p

  Study phs001414

• Genetic Analysis of Tuberous Sclerosis Complex (TSC) Hypomelanotic Macules

  In this study we searched for mutations in the TSC1 and TSC2 genes in cultured melanocytes from individuals with the genetic disease Tuberous Sclerosis Complex.

  Study phs001236

• Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

  In this study, we used two independent single-cell whole-genome sequencing methods, Tn5-transposase-based amplification (TbA) and primary template amplification (PTA), to profile somatic copy number variants (CNVs) in single cortical neurons from postmortem human brain donors ranging from gestational week 14 to over 89 years of age, complemented by single-nucleus multiome (ATAC- and RNA-seq) profiling of a subset of the same donors. We found that widespread, multi-chromosomal CNVs were present in up to 46% of prenatal neurons, but this proportion dropped four- to five-fold after birth. Neurons with widespread CNVs were eliminated mostly around the time of birth, while neurons carrying smaller CNVs continued to be cleared more gradually throughout postnatal life. CNV breakpoints tracked closely with DNA replication timing, and recurrent copy losses were associated with double-strand break hotspots, implicating replication stress and NHEJ-mediated repair in dividing progenitor cells as sources of these lesions. Consistent with chromosome missegregation during development, we also observed micronuclei containing missegregated chromosomal material in the prenatal cortex, with micronuclear genomic content declining with age in parallel with the loss of CNV-bearing neurons. Neurons with a high CNV burden showed dysregulated synaptic gene expression and increased cell-death pathway activity, and the genomic regions spared from CNVs in surviving neurons were enriched for autism-risk and postsynaptic genes, evidence that this elimination is selective rather than random. Together, these findings suggest that clearance of genomically defective neurons, coupled to synapse formation, acts as a genome quality-control mechanism across brain development and aging. Through this accession, we are releasing single-cell and bulk whole-genome and multiome sequencing data for the postmortem brain donors and one iPSC-derived reference line.

  Study phs004946

• Pharmacogenomics of Statin Therapy (POST)

  A central goal of the Pharmacogenomics of Statin Therapy (POST) study was to identify genetic and other factors that contribute to the clinical efficacy and adverse effects of statins. Approximately 700 Kaiser Permanente of Northern California (KPNC) members who were current or former statin users were recruited as POST participants based on their electronic health record (EHR) data. Some participants experienced myocardial infarction while on statins, developed dysglycemia while on statins, and/or had myopathy symptoms while on statins, while the remainder were “unaffected” statin-treated controls. Genotype array data was generated from almost all POST participants, and induced pluripotent stem cells (iPSCs) were created for a subset of POST participants for in vitro statin exposures and transcriptomic analysis.

  Study phs003596

• African American Cardiovascular Pharmacogenomics Consortium (ACCOuNT)

  The African American Cardiovascular Pharmacogenomics Consortium (ACCOuNT) assembled an observational cohort to characterize genetic and clinical determinants of inter‑individual variability in warfarin dose requirements among participants of African ancestry receiving anticoagulation care. The submission includes individual‑level genotypes in PLINK format (.bed/.bim/.fam) and a harmonized phenotype file with stable warfarin dose, age, height, weight, and concomitant medication indicators (aspirin, amiodarone) for 309 participants. Biospecimens are germline DNA from peripheral blood; no tumor samples and no case–control disease labels are involved. The resource is intended to enable discovery and validation of pharmacogenomic loci, development of dose‑prediction models, and methods benchmarking focused on underrepresented populations. Data available through dbGaP comprise the genotype files, the subject‑level phenotype dataset, and minimal sample metadata needed to link subjects to biospecimens.

  Study phs004279

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Brain and Genetic Predictors of Placebo Analgesia

  Design: Observational, population twin-based cohort study conducted at the University of Colorado, Boulder. Primary Aim: To investigate how genetics and brain function jointly influence individual differences in pain perception and placebo response, using thermal and mechanical experimental pain protocols and measuring neural responses via fMRI.Outcome Measures: Pain ratings on a Visual Analog Scale (VAS) from 0 (no pain) to 100 (most intense pain imaginable) during pain tasks. These ratings were taken during a single four-hour experimental session. Phenotypic data is shared for 460 individuals, and genotypic data is shared for 247 of the 460 individuals.Data from this study are also available from OpenNeuro.org.

  Study phs002118

• Genetic Basis of Early Onset Bicuspid Aortic Valve Disease

  The study protocol was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (HSC-MS-11-0185). Study recruitment began on July 1, 2017, and concluded on March 30, 2022. After written informed consent, we enrolled probands with early onset BAV disease (EBAV), which we defined as individuals with BAV who were under the age of 30 at the time of first clinical event. Clinical events were defined as aortic replacement, aortic valve surgery, aortic dissection, moderate or severe aortic stenosis or aortic regurgitation, large aneurysm (Z > 4.5), or intervention for BAV-related conditions. Those with hypoplastic left heart, known genetic mutations, genetic syndromes, or complex congenital heart disease were excluded. Samples were collected and genotyped as previously reported. For comparison, we analyzed a cohort of older individuals of European ancestry with sporadic BAV disease selected from the International BAV Consortium (BAVGWAS). Phenotypes were derived from record review with confirmation of image data whenever possible [25-26]. The computational pipeline for CNV analysis of Illumina single nucleotide polymorphism (SNP) array data included three independent CNV detection algorithms.GenomeStudio was used to exclude samples with indeterminate sex or more than 5% missing genotypes, and single nucleotide polymorphisms (SNPs) with GenTrain = 0. Principal component analysis was used to remove outliers that did not cluster with European ancestry. Prior to CNV analysis, each dataset was trimmed by selecting a common set of 650,000 SNPs that were genotyped on each of the microarrays used in this study.Three independent algorithms (PennCNV, cnvPartition, and QuantiSNP) were used to generate CNV calls and sample-level quality statistics from SNP intensity data. PennCNV and QuantiSNP were run on Unix clusters and cnvPartition data were exported from GenomeStudio. The analysis was run using default configurations. PennCNV was used to generate QC data and remove CNV calls that intersect with polymorphic genomic regions. Samples that met any of the following criteria were excluded, standard deviation of the LogR ratio (obtained from PennCNV) > 0.35 or number of CNVs > 2 standard deviations above the mean for each data set. CNV calls less than 20 Kilobases in length and/or spanned by fewer than 6 probes were excluded. The overlap function for rare CNVs in PLINK was used to construct CNV regions (CNVRs) after adjacent regions were merged using PennCNV. LogR ratio (LRR) and B allele frequency (BAF) data at CNVRs and calls of interest were visualized in GenomeStudio for validation. For segregation analysis, GenomeStudio was used to determine the presence of CNVs in relatives.A total of 22,014 unselected control Illumina Genotypes obtained from the Database of Genotypes and Phenotypes were analyzed using identical methods (S1 Table). The Wisconsin Longitudinal Study (WLS) includes data on a cohort of 10,300 individuals who graduated from Wisconsin high schools in 1957. The Health and Retirement Study (HRS) includes data on 37,000 individuals aged 50 above from 23,000 households across the United States. Principal component analysis was used to select European ancestry genotypes from these datasets for analysis. Datasets were paired for case-control analysis based on the concordance of log-transformed sample-level quality control statistics (number of CNV calls and standard deviation of logR ratios). Chi-squared or Fisher exact tests were used to compare CNV frequencies in cases and controls.Rare CNV functions in PLINK (v1.7) were used to perform permutation-based burden tests or gene set-based enrichment tests. Case control burden tests were restricted to CNVs that were longer than 110 Kb and less than 0.1% in frequency. CNV overlap functions in PLINK were used to identify rare CNVs that intersect between datasets or involve specific BAV or CHD genes . The list of candidate genes included 190 CHD genes that have strong cumulative evidence to cause BAV or related congenital malformations from human or animal model data. Genome Reference Consortium Human Build 37 was used for CNV annotation [34].

  Study phs003705

• Whole Exome Sequencing of PCOS

  Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of reproductive age and is characterized by hyperandrogenism, oligomenorrhea/amenorrhea, and polycystic ovaries. The goals of this project were to 1) generate a comprehensive catalog of likely causal PCOS associated variants, 2) establish the functional consequences of the genetic variants identified by whole exome sequencing (WES) using bioinformatic and molecular strategy, and 3) identify genes and molecular pathways that are genetically impaired in PCOS with the goal of providing more targeted treatment for PCOS. To achieve these goals, we carried out WES on a total of 1064 samples corresponding to 1049 unique subjects (15 subjects had duplicate sequencing samples). The samples include 731 PCOS cases (731 unique), 318 controls (309 controls), and 15 samples of unknown phenotype (6 PPCOSII, 9 HapMap controls). Controls are reproductive age women with normal androgens and regular menses as phenotype control. We designed a Custom WES array which includes the standard CIDR WES array plus 9.8 Mb of Twist Custom Design added content encoding genomic regions in linkage disequilibrium with PCOS associated GWAS regions. Sequencing was performed at the Center for Inherited Disease Research (CIDR), Johns Hopkins University School of Medicine. Target templates are sequenced to >100x coverage using paired-end reads on the Illumina NovaSeq6000 platform.

  Study phs004025

• DNA Termini Correlate with Methylation at CpG Sites in Hair, Urine and Blood Plasma Cell-Free DNA

  The aim of this study was to reconstruct the age of individuals from cell-free DNA (cfDNA) present in rootless hair and urine samples using epigenetic clock methods. Hair was chosen as a noninvasive source for biological age estimation and a sample type which is relevant in forensic science. Samples were obtained from anonymous volunteers. The study expands epigenetic clock research to hair tissue and provides a resource for modeling age-related changes in CpG methylation. Whole genome shotgun sequencing data was generated for all samples using a single-stranded library preparation.

  Study phs004104

• Association Between Telomere Length and Falciparum Malaria Endemicity in Sub-Saharan Africans

  The goal of this study was to identify the genetic and environmental drivers of telomere length variation in an ethnically diverse African cohort. It comprises 1,818 participants from Cameroon, Tanzania, Ethiopia, and Botswana. For each participant, leukocyte telomere length was measured using the Southern blotting of the terminal restriction fragment methodology. 1,758 of the individuals with phenotype data also had genetic data, and these individuals were subjected to a genome-wide association study which accounted for age, sex, and genetic relatedness. Individuals were genotyped on one of two genotyping arrays (Illumina Infinium Omni5 array or Illumina H3Africa consortium array). Genetic datasets were merged, and missing genotypes were imputed for a final genetic dataset of 11,001,107 genetic variants. Correlations between telomere length and a variety of environmental factors, including malaria endemicity, were also examined in this study.

  Study phs003567

• Epigenetic Damage in Women Living in LA Food-Desert Zip Codes

  This study investigated the impact of insulin resistance on chromatin acetylation and inflammation. Blood samples were obtained from women consented to City of Hope Institutional Review Board (IRB)-approved COH Protocol#/Ref#:18306/158149. Women provided demographic information and completed a survey assessing diet, housing and medical history. BMI was obtained from medical records. HgbA1c was measured and cytokine arrays were used to measure serum TNFalpha, IL6, IL15, IL16, IL23, Leptin, and CXCL1.

  Study phs003522

• A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

  This study investigated the genomic landscape of tumors from patients with inherited mutations in DNA repair genes. The aim of this study was to determine the relationship between locus-specific loss of heterozygosity (LOH) and genomic signatures of homologous recombination-based DNA repair (HR) deficiency in tumors associated with pathogenic germline variants in DNA repair genes. Cohorts of pathogenic germline variant (PGV) carriers with different cancer types were identified via a cancer genetics registry and clinical practice at Penn Medicine and through our collaborator network. Tumors were analyzed with next generation sequencing (whole exome and/or targeted panel sequencing) with or without transcriptomic analyses. Sub-study #1 "Non-breast/ovarian tumors in germline BRCA1/2 carriers". This study investigated primary non-breast/ovarian tumors that arise in individuals with BRCA1/BRCA2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Individual WES data from DNA samples from tumor and normal are available. Sub-study #2: "Breast tumors in germline CHEK2 carriers". This study investigated primary breast tumors that arise in individuals with CHEK2 pathogenic germline variants (PGVs). Whole exome sequencing (WES) using Agilent All-Exon Kit v7 hybrid capture probes was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors. Individual WES data from DNA samples from tumor and normal and RNAseq data from tumor are available. Sub-study #3: "Breast tumors in germline TP53 carriers". This study investigated primary breast tumors that arise in individuals with TP53 pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal breast tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available. Sub-study #4: "Prostate tumors in germline DNA repair carriers". This study investigated prostate tumors that arise in individuals with a variety of pathogenic germline variants (PGVs). Whole genome sequencing (WGS) and/or custom panel targeted sequencing was performed on matched tumor and blood germline normal DNA on an Illumina HiSeq. Whole transcriptome RNAseq was performed on tumors and normal prostate tissue. Individual WGS or targeted data from DNA samples from tumor and normal and RNASeq data from tumor and normal are available.

  Study phs003348

• Regulation of T Cell CXCL13 Production

  This study evaluated the signals that regulate production of the B cell chemoattractant CXCL13 by human CD4 T cells. Single-cell and bulk RNA-seq datasets evaluated the gene expression changes induced by TGF-beta and the aryl hydrocarbon receptor (AHR), two signals that regulate CXCL13 production. Bulk ATAC-seq data evaluated the epigenetic changes in T cell stimulated with an AHR agonist or antagonist. Ex vivo bulk RNA-seq data of sorted T cell subsets from blood of patients with lupus and control donors interrogated the gene expression differences in sorted T cell subsets. Ex vivo ATAC-seq data allowed comparison of epigenetic profiles of PD-1hi Tph cells from rheumatoid arthritis synovial fluid and PD-1hi T follicular helper (Tfh) cells from tonsil to PD-1low CD4 T cells from the same samples. Single-cell RNA-seq data of T cells from lupus patients before and after treatment with anifrolumab (anti-IFNAR) allowed interrogation of T cell populations that change with anifrolumab treatment. These datasets allowed for genomic interrogation of changes induced by AHR, TGF-beta, and interferon and their relationship to CXCL13 production.

  Study phs003582

• Targeting EGFR in NF1 Mutant Melanoma

  Our study focused on melanoma patients with driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene, a subset of melanoma patients that have not benefitted from recent treatment advances. We have leveraged patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could be developed into therapies for NF1 mutant melanoma patients. Our studies revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, and that genetic or pharmacological EGFR inhibition impaired tumor cell proliferation, survival, and cell growth in patient-derived NF1 mutant but not NF1 wild-type melanoma models.

  Study phs003906

• dbGaP Collection: Compilation of Individual-Level Genomic Data for General Research Use

  This dbGaP Collection contains all authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level GRU datasets that become available. Renewal of this study is required annually. Data Included in this Study Individual-level genomic data designated for general research use with no further use limitations or restrictions, that is, Data use does not require approval by an Institutional Review Board for secondary analyses Data have no publication embargo Data have no other use limitations (e.g., requirement for collaboration or publication; restricted for use by academic or not-for-profit organizations; restricted to health, medical, and/or biomedical research) In response to requests from the scientific community, the NIH implemented a change in the procedures for accessing individual-level GRU genomic data. Under the modified procedures, interested investigators can request GRU individual-level genomic datasets with a single application. However, please note that these data have not been harmonized. Additionally, to help expedite the processing of requests for individual-level GRU genomic datasets, the requests will be reviewed by a single, central Data Access Committee. The process for requesting these datasets is identical to the request process for non-GRU individual-level, controlled-access data, such as the expectation that investigators will abide by the NIH Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies and Data Use Certification Agreement. Effective April 24, 2018, the Data Use Limitations (DUL) for the Genes and Blood Clotting Study (GABC) (phs000304) was updated to Health/Medical/Biomedical, Not-for-profit Use Only (HMB-NPU). Additionally, the submitting institutions have requested the removal of the National Heart, Lung, and Blood Institute (NHLBI) "Grand Opportunity" Exome Sequencing Project (GO-ESP) Lung Cohorts Exome Sequencing Project: Genetic modifiers of Pseudomonas aeruginosa (Pa) lung infection acquisition in cystic fibrosis (phs000254) from the dbGaP Compilation of Individual-Level Genomic Data for General Research Use (dbGaP Compilation) (phs000688). As such, data from studies phs000304 and phs000254 are no longer available as part of the dbGaP Compilation (phs000688). Investigators must submit separate Data Access Requests (DARs) for the two studies and be approved by the NHLBI Data Access Committee.

  Study phs000688

• SCORCH: Single Cell Transcriptomic and Epigenomic Dissection of Opioid and Cocaine Responses in HIV

  Substance use disorder (SUD) is a common and debilitating condition characterized by compulsive use of an addictive substance, inability to control use of this substance, and the emergence of withdrawal symptoms in the absence of the substance. Despite great advances in our understanding of changes that occur in various brain regions in the context of addiction/SUD, we have a limited understanding of the diversity of cell types and gene expression profiles of cells within affected human brain regions, and how exposures to addictive substances, such as opioids and cocaine, influence the molecular properties and functions of these cells. Over 50% of HIV-infected patients experience neurological disorders, collectively termed HIV-Associated Neurocognitive Disorders (HAND) that range from the asymptomatic neurocognitive impairment to severely disabling dementia. The use of addictive substances by HIV-infected individuals has been linked to diminished immune function, increased neuroinflammation and neuronal injury, and exacerbation of HAND. Here, we seek to directly dissect the common and distinct molecular bases of SUD/HIV infection/HAND effects on distinct cell types by systematic profiling, dissection, computational integration, and experimental validation of their transcriptional, epigenomic, and genetic signatures across individuals, brain regions, and cell types. Aim 1: We use genetic, epigenomic, and transcriptional profiles, generating a total of ~28 million genome-wide maps at the single-cell (sc) level using 2,800 samples with 10,000 cells per sample; these span 7 brain regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, dorsal striatum, insula, amygdala, hippocampus), two assays (scRNA, scATAC), four phenotypic groups (SUD+/HIV+, SUD+/HIV-, SUD-/HIV+, SUD-/HIV-), and a total of 200 subjects (50 in each phenotypic group). Aim 2: We integrate these datasets to predict driver genes, regulatory regions, variants, and pathways, and the cell types and brain regions where they act. Aim 3: We validate high-priority findings at the molecular level, and functionally validate the highest priority targets' ability to modulate addictive behaviors in mouse models of in vivo cocaine self-administration. The resulting datasets will help guide the search for new therapeutics by providing detailed therapeutic targets and the specific conditions where they are predicted to act.

  Study phs004675

• Lung Tissue Research Consortium (LTRC-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 LTRC include DNA, Plasma, Serum, Tissue - FFPE Cassettes, Tissue – RNALater Frozen, and Tissue - Snap Frozen. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The LTRC was a biobank resource established by the NHLBI to collect and distribute lung tissue, blood samples, clinical data, and radiographic studies from participants with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), other related idiopathic interstitial pneumonias (IIP) and interstitial pneumonias associated with connective tissue diseases who undergo medically-indicated lung resection. All tissue and blood specimens and clinical data were banked centrally and stored for distribution to external investigators who have approved study proposals to investigate the pathogenesis or management of lung diseases. The ultimate goal of this program was to enable research that illuminates the pathobiology of lung diseases and leads to novel interventional treatments for these conditions. Background: Chronic lung diseases are a main cause of death and disability in the United States. COPD affects over 14 million individuals in the United States and represents the third leading cause of mortality. Cigarette smoking is a major risk factor. However, only one of six individuals who smoke develops COPD. This could imply either an individual susceptibility or an additional immunologic or infectious injury to lung cells. Current treatments offer symptomatic relief, but do not prevent disease progression. Better understanding of disease pathogenesis, including the potential roles of lung parenchymal cell apoptosis, immunologic injury, and inflammation may lead to therapies that improve survival and quality of life. Interstitial pneumonias, including IPF and those associated with connective tissue disease, are less common than COPD, but for many of these diseases there are poor outcomes. For example, IPF has a 50% survival rate 2-3 years following diagnosis, and currently no treatment exists which prolongs survival. The prevalence of IPF is approximately 28 cases per 100,000. The underlying histology of IPF is usual interstitial pneumonia (UIP), which can also occur in connective tissue diseases. The incidences of other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP) or acute interstitial pneumonia (AIP) are less frequent but also occur as an expression of interstitial lung disease in the connective tissue diseases. Moreover, there is significant crossover of these three interstitial pneumonias so that cases of IPF/UIP may also reveal fibrotic NSIP and be complicated by episodes of AIP. This implies common injuries but dissimilar histological responses. All of these processes are characterized by epithelial injury, uncontrolled fibroproliferation and the deposition of collagen, irrespective of the histology. It is clear that a better understanding of the genesis of the interstitial pneumonias is required before effective interventions can be developed. Participants: A total of 4,486 participants were enrolled, and lung tissue was obtained from 3,333 of these participants.Design: Written informed consent of each participant was required before any LTRC procedure was performed. Phenotypic data were then obtained that included recording of relevant medical information, a limited exposure history, radiological evaluation, and pulmonary physiological and lung function testing. Questionnaires were administered to determine the extent of symptoms, associated medical illnesses, smoking, environmental and occupational exposures, and quality of life. Laboratory testing included pulmonary function testing, a six-minute walk test, and chest x-ray CT. Blood specimens were collected both for defining the clinical phenotype of donors and to obtain serum, plasma, and DNA for later investigative purposes. At the time of surgery, lung tissues were collected and processed for long-term storage. The LTRC collected only the 'non-tumorous' portions of lung tissue from surgical procedures performed for primary or metastatic lung tumors and received those specimens only after the local pathologist had procured all tissue required for clinical care. Samples of appropriate size were cut and placed in formalin, RNAlater, glutaraldehyde, or liquid nitrogen within 30 minutes of excision (approximately 5% of cases exceeded this target time). Blood and tissue specimens were subsequently shipped to a central Tissue Repository for further processing and long-term storage. A Radiology Center provided quality control and quality assessment of CT data. A Data Coordinating Center managed study operations and maintained a repository of study data. Conclusions: LTRC established a biospecimen collection that is unique in its size, diseases included, standardization of methods, and extent of phenotypic data, serving as a valuable resource to facilitate research on the pathobiology of lung diseases.

  Study phs003913

• Cellular and Molecular Profiling of Epithelial Ovarian Cancers and Associated Normal Tissues

  This collection of data includes bulk RNA-seq and whole genome bisulfite sequencing (WGBS) for ovarian cancer samples (microdissected into carcinoma and stroma compartments), as well as single-cell RNA-seq (scRNA-Seq) and bulk WGBS and enzymatic methyl-seq (EM-seq) normal human Fallopian tube samples. The data from the ovarian cancer samples was collected to understand cellular and molecular alterations associated with histological and molecular subtypes of ovarian cancer. Data for these samples are included in Djirackor, Heinze et al. (accepted at Cancer Research). The scRNA-Seq data was generated to identify the developmental trajectory, cell type composition, and point towards the cell-of-origin for high grade serous ovarian carcinoma (HGSOC). Further, this was intended to establish a normal RNA reference for the cancer data. Results from this study are described in Johnson, Majewski et al. (accepted at Nature Communications, preprint PMID: 40475517). The data from bulk DNA methylation on normal Fallopian tubes was used to optimize the bisulfite-conversion process for the cancer samples and to serve as an epigenetic reference in the cancer studies. This data is described in Morrison et al. (PMID: 34147133). Any questions can be directed to Hui Shen (hui.shen@vai.org).

  Study phs004702

• Impact of Genetic Variation on Response to GO Therapy in COG-AML Trials AAML03P1 and AAML0531

  The 340 de novo Acute Myeloid Leukemia (AML) patients (ages 1 month to 21 years) were enrolled in COG-AAML03P1 (NCT00070174). Everyone received standard chemotherapy regimen of ara-C, daunorubicin and etoposide (ADE) with addition of one 3 mg/m2 dose of Gemtuzumab Ozogamicin (GO) in induction 1 as well as in intensification II phase. The 1022 de novo AML patients (ages 0–30 years) were enrolled in COG-AAML0531 (NCT01407757). They were randomly assigned to receive either the standard ADE regimen (ADE arm, n = 511) or with the addition of one 3 mg/m2 dose of GO, during induction I as well as intensification II phase (ADE+GO arm, n = 511). Detailed study design, treatment regimen, and clinical outcomes of these two trials have been previously published (Cooper TM, Franklin J, Gerbing RB, et al., PMID:21766293 and Gamis AS, Alonzo TA, Meshinchi S, et al., PMID:25092781). The current study used genomic DNA from 1,225 pediatric patients treated in these two trials with 470 patients treated with standard chemotherapy in COG-AAML0531 (ADE arm) and 755 patients treated with addition of GO to standard therapy in COG-AAML03P1 and COG-AAML0531 trials (ADE+GO arm). The 132 SNPs in 42 genes within DNA-damage repair (DDR) pathways or genes implicated in mediating calicheamicin were selected for genotyping. These SNPs were genotyped using the Sequenom platform at the Biomedical Genomics Center, University of Minnesota. All SNPs had a call rate of more than 0.98 and were in accordance with the Hardy–Weinberg equilibrium. These genotypes were used to test for association with clinical endpoints as defined in the COG-AAML03P1 and COG-AAML0531 trials.

  Study phs003490

• Blood and Marrow Clinical Trials Network Evaluating Corticosteroids with Mycophenolate Mofetil vs. Corticosteroids with Placebo as Initial Systemic Treatment of Acute GVHD (BMT-CTN-0802-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.ObjectivesExplore the difference in response and survival rates for individuals with acute graft versus host disease (aGVHD) who received mycophenolate mofetil (MMF) plus corticosteroids versus corticosteroids alone.BackgroundIndividuals with certain cancers, genetic blood diseases, autoimmune diseases, and skeletal dysplasia may be candidates to receive an allogeneic hematopoietic stem cell transplantation (HSCT) as a potentially curative measure. A common and often fatal complication of receiving the transplant is acute graft-versus host disease (aGVHD). Historically, aGVHD has been treated with corticosteroids alone but favorable response rates are less than half prompting the need for better treatment options.ParticipantsAdult and pediatric participants were eligible for this study if they were the recipient of an allogeneic HSCT and newly diagnosed with aGVHD. Participants also needed to be able to swallow the MMF or placebo capsules and have an absolute neutrophil count > 500 cells per μL without growth factors. Disqualifiers for study eligibility included receipt of MMF or mycophenolic acid within 7 days of screening, uncontrolled infections, hepatic veno-occlusive disease, chronic GVHD, or renal failure on dialysis.A total of 235 patients participated in the study. Participants were randomized into either a treatment or placebo group. There were 116 participants in the treatment or MMF arm and 119 participants in the placebo arm.DesignBMT CTN 0802 was a phase 3 multicenter randomized double-blinded trial. Randomization was stratified by transplant center and grade of aGVHD (I-II vs III-IV) at study entry. Eligible participants who required GVHD therapy were treated within 72 hours of enrollment. All patients in the study received corticosteroids at a dose of prednisone 2 mg/kg per day orally (or methylprednisolone 1.6 mg/kg per day IV). Patients were also given MMF or the placebo at a dose of 1000 mg or 20 mg/kg (for patients Response to treatment was classified as complete, partial, progression, no response, or flare. Complete response (CR) was defined as complete resolution of all signs and symptoms of aGVHD, and a partial response (PR) was defined as improvement of 1 stage in 1 or more organs involved by GVHD without progression in others. Progression was defined as worsening in 1 or more organs, and no response was defined as stable disease or absence of improvement in any organ involved by GVHD within 14 days of therapy initiation. A flare in GVHD was defined as any increase in symptoms or therapy for aGVHD after an initial response (CR or PR). All toxicities were reported regardless of whether they were thought to be related to the study treatment.Adult study participants who were able to communicate in English also completed the MD Anderson Symptom Inventory (MDASI), a tool used to measure quality of life. Participants completed the inventory at enrolment and at day 56 ± 7 days.The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy.ConclusionsResults for this study concluded that the addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. There was also no difference between the treatment arms in regards to quality of life measures (Bolanos-Meade J, Logan B, Alousi A et al., Blood. 2014;124(22):3221-3227).

  Study phs004840

• Tracking Therapy-Resistant Alterations in Childhood Acute Lymphoblastic Leukemia

  Relapse is currently the major cause of death in children with B-ALL. The goal of this study is to uncover the genetic underpinnings of relapsed B-ALL in the AALL1331 cohort (PMID: 33651090) via whole genome and transcriptome sequencing of matched diagnosis, relapse, and remission specimens. We aim to discover genetic alterations that drive treatment resistance in relapsed tumors. We also aim to investigate the feasibility of detecting residual tumors from remission samples with the ultimate goal to improve risk stratification using NGS-based minimal residual disease (MRD) detection. Here we only report data from patients in remission with the aim of determining MRD. We will submit corresponding data for the diagnosis and relapse components of our cohort in a future version of our study.

  Study phs003409

• National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III): Survey (Phenotype) Data Only

  This study includes survey (phenotype) data only from the National Epidemiologic Survey on Alcohol and Related Conditions–III (NESARC-III), comprising 36,309 participants and 4,053 phenotypic variables. Individual-level genetic data (N = 22,848 participants), along with corresponding phenotypic variables, are available through a separate dbGaP study (accession: phs001590). NESARC-III is a nationally representative, cross-sectional survey of the U.S. general population, sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and conducted in 2012–2013. The target population comprised noninstitutionalized U.S. civilians aged 18 and older, including residents of selected group quarters (e.g., group homes and workers' dormitories). Respondents were selected using multistage probability sampling: primary sampling units (PSUs) consisted of individual counties or groups of contiguous counties; secondary sampling units (SSUs) comprised Census-defined block groups; and tertiary sampling units were households within SSUs, from which eligible adults were randomly selected. Hispanics, Blacks, and Asians were oversampled. The final sample included 36,309 respondents, all of whom provided informed consent. To account for the complex survey design, analyses should incorporate design variables and sampling weights. Users should specify the following in SAS, Stata, or R: Cluster variable: VARUNIT Strata variable: VARSTRAT Weight variable: AUDWEIGHT NESARC-III collected detailed information on alcohol and drug use, substance use disorders, psychiatric disorders, physical health conditions, and related risk factors. The dataset also includes extensive sociodemographic variables (e.g., age, sex, race/ethnicity), adverse childhood experiences (e.g., sexual abuse, physical abuse, neglect), family history of substance use and psychiatric disorders, and other environmental risk factors, totaling 4,053 phenotypic variables. Please refer to the supporting documents (e.g., the codebook and questionnaires) for definitions, descriptions of the phenotypic variables, and additional details. The supporting documents can be found in Documents tab in dbGaP or NIAAA website (https://www.niaaa.nih.gov/research/data-archive-resources/niaaa-controlled-datasets/nesarc-iii-study).DSM-5 diagnostic assessments cover the following conditions: Substance Use Disorders: Alcohol use disorder Nicotine use disorder Cannabis use disorder Cocaine use disorder Opioid use disorder Mood Disorders: Major depressive disorder Persistent depressive disorder (dysthymia) Bipolar I disorder Bipolar II disorderAnxiety Disorders:Panic disorder Agoraphobia Social anxiety disorder (social phobia) Specific phobia Generalized anxiety disorder (GAD) Trauma-Related Disorder:Posttraumatic stress disorder (PTSD) Personality Disorders: Schizotypal personality disorder Borderline personality disorder Antisocial personality disorder Eating Disorders: Anorexia nervosa Bulimia nervosa Binge-eating disorder

  Study phs004548

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• Feasibility of Circulating 5-Hydroxymethylcytosine Profiling in Osteosarcoma

  Aims: To examine the utility and performance of 5-hydroxymethycytosine (5-hmC) profiling of cell-free DNA (cfDNA) as a biomarker of disease in patients with osteosarcoma. Population: A Discovery cohort consisting of 5 patients with primary, localized osteosarcoma and an independent Validation cohort consisting of 17 patients with osteosarcoma. Serial cfDNA samples were collected for the majority of patients.Molecular Technologies Employed: Nano-hmC-Seal libraries were constructed from 1-10 ng of cfDNA. Briefly, cfDNA 5-hmC marks were subjected to enzymatic modification with UDP-N3-glucose, followed by chemical modification with biotin. Biotin-labeled cfDNA fragments were then pulled down using streptavidin beads, and PCR amplified to construct sequencing libraries. Findings: Using genes with differential 5-hmC deposition between osteosarcoma patients at diagnosis in the Discovery cohort and well children, hierarchal clustering identified two clusters of samples in the Validation cohort that were associated with disease status. Using a semi-quantitative osteosarcoma signature scoring system, the sensitivity and specificity to identify patients with active disease were 65% and 64%, respectively. Lung/soft tissue metastases were not readily identified. Despite limitations, 5-hmC profiling of cfDNA is feasible as a technique and further investigation with larger patient cohorts is warranted.

  Study phs003842

• CIDR NICHD Genetic Basis of Recessive Pediatric Brain Diseases - Group 4

  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 (WES) 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 phs001822

• Genetic Markers of Caries Risk in Diverse Underserved Children: CIDR

  The study Predicting Caries Risk In Underserved Children, From Toddlers To The School-age Years In Primary Healthcare Settings, is a renewal of an initial project designed to develop a dental caries risk tool for use in primary medical and dental healthcare settings to identify high dental caries risk children, expanding from the toddler (1-4 years old, referred to as Stage 1 grant) to the school-age years (6-9 years old, referred to as Stage 2 grant); and to determine the relationships between dental caries risk profiles and dental caries disease patterns. 1326 children, 12 +/- 3 months of age, and their primary caregivers, were enrolled in the study. This cohort represents a diverse population, including ethnic and racial minorities and low socio-economic status groups. There are a total of six in-person visits (at child age 1, 2.5, 4, 6.5, 8 and 9.5 years), and at each one the primary caregiver (PCG) completes a dental caries risk questionnaire, and the child receives a detailed dental caries examination. Saliva samples were collected during the age 8 visit (2019-2020) from 1,059 racially and ethnically diverse individuals (543 children and 516 PCGs) for the purposes of human genetic testing, to study the genetics of dental caries experience of children and their primary caregivers.

  Study phs003280

• Diabetic Retinopathy Genomics Study (DRGen) - Genetic Biomarkers of Diabetic Retinopathy

  Using a well-defined, clinically supported phenotypic strategy, we seek to better understand the role of common and rare genetic variants in the progression of diabetic retinopathy (DR). Whole exome/whole genome sequencing (WES/WGS) was used to systematically search the human genome to detect DR susceptibility genes or genes that protect people from developing advanced DR. Clinical data and bio specimens were obtained from clinically defined DR phenotypes such as, (i) No/Mild NPDR (non-proliferative DR) with a subset of extreme phenotype, ii) Diabetic macular edema (DME) alone and iii) Proliferative diabetic retinopathy (PDR) alone. In this ongoing comprehensive genomic study, we wish to i) Identify potential common and rare variants that may influence the phenotypic differentiation of DR into DME or PDR, ii) Define genetic variants stratified based on the "extreme phenotype," and iii) Characterize genetic factors that determine the differential response to anti-VEGF drugs in DME patients. Definition of Diabetic Retinopathy and classification of groups Study 1. Proliferative diabetic retinopathy (PDR). Anybody showing evidence of retinal neovascularization on the disc (NVD) or elsewhere (NVE) with or without pre-retinal and vitreous hemorrhage will be considered PDR. We will include only those "active" PDR patients. The total number of consented subjects in this study is 182. Study 2. Isolated Phenotype: Varied response with anti-VEGF treatment is a significant limiting factor for better clinical outcomes. We quantify the response to anti-VEGF treatment based on visual acuity changes and anatomic features of DME assessed by optical coherence tomography (OCT). Depending on the response at one month following three monthly intravitreal anti-VEGF injections, we have observed two phenotypes: 1) Good responders: Participants were considered "good responders" if the anatomical outcome to anti-VEGF treatment resulted in a significant reduction of baseline central retinal thickness (CRT) > 25% after three anti-VEGF injections. 2) Poor Responders: Participants were classified as "poor responders" if the outcome of anti-VEGF treatment resulted in a reduction of CRT < 20% or in any increase in CRT after three monthly injections. The total number of consented subjects in this study is 17.

  Study phs002501

• CIDR: Whole Exome Sequencing of Multiple Myeloma

  This goal of this project is to perform systematic analyses of germline genetic alterations in sporadic and familial multiple myeloma (MM) to discover candidate genes from these exome data. In this proposal, we will build on our prior work and pre-existing genomic data to prioritize, identify and validate novel candidate genes conferring susceptibility to MM.

  Study phs002497

• Single-Cell Mitochondrial Mutation Lineage Tracing of Non-Dysplastic and Dysplastic Barrett's Esophagus

  This study addresses a critical knowledge gap in understanding Barrett's esophagus (BE), a common metaplastic condition and precursor to esophageal adenocarcinoma, by identifying lineage connections and cell states underlying its development and malignant transformation. We collected biopsies from 13 Barrett's esophagus patients undergoing routine surveillance endoscopy, sampling metaplastic tissue alongside normal squamous esophagus and gastric cardia tissues when clinically appropriate. Our novel approach integrated single-cell RNA sequencing of nearly 180,000 cells with mitochondrial DNA mutation analysis for lineage tracing, coupled with spatial transcriptomics and comprehensive whole-exome sequencing. For one patient with high-grade dysplasia, we performed detailed whole-exome sequencing analysis at 100x coverage on dissociated Barrett's esophagus cells alongside matched normal esophagus and gastric cardia tissues. This genomic profiling revealed critical genetic drivers of malignant transformation, including a truncating mutation in the mutation cluster region of APC (a negative WNT regulator), mutations in the tumor suppressor genes CDKN2A and TP53, and significant copy number alterations including loss of CDKN2A on chromosome 9. These genetic alterations corresponded with the transcriptional changes observed in our single-cell data, particularly WNT pathway dysregulation and the expansion of LGR5-expressing stem cells, providing molecular evidence for how single clones can initiate the dysplastic transformation. Data deposited in dbGaP consist specifically of the whole-exome sequencing raw files, processed variant calls, and copy number analyses from the single patient with high-grade dysplasia and matched normal esophagus and stomach control tissue. Whole exome sequencing was performed on an Illumina NovaSeq 6000. Sequencing data was preprocessed following the Genome Analysis Toolkit's (GATK) Best Practices. Sequencing data was analyzed with Mutect2 (GATK, v4.2.5.0) to identify short somatic mutations including single-nucleotide polymorphisms and insertions and deletions. The Barrett's esophagus sample was run with the two matched normals, as well as the publicly available germline resource somatic-hg38_af-only-gnomad.hg38.vcf.gz (GATK). Somatic variant calls were filtered using FilterMutectCalls (GATK) and loaded into the Integrative Genomics Viewer (v2.12.3) for identification of high-quality variants in known esophageal adenocarcinoma regulators. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9). CNV, Mutect2, and SVC analyses will be made available through dbGAP. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9) with the default run settings; a pooled reference was generated from the normal esophagus and stomach samples. Copy number results were plotted directly within CNVkit using the function scatter.

  Study phs003949

• The Contribution of De Novo Coding Mutations to Meningomyelocele

  Meningomyelocele (MM) is considered a genetically complex disease resulting from the failure of the neural tube to close; a neural tube defect (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but most risk remains unexplained. 851 MM trios were recruited and we found 187 likely gene disrupting or damaging missense de novo mutations (DNMs) that are estimated to contribute to disease risk. These DNMs collectively define networks including actin cytoskeleton and microtubule-based processes, axon guidance, and histone modification. Gene validation demonstrates partial or complete loss of function, impaired signaling and defective neural tube closure in Xenopus embryos. Our results suggest DNMs make key contributions to MM risk, and highlight critical pathways required for neural tube closure in human embryogenesis. Data for 245 WES trios and 1 quad are available through dbGaP.

  Study phs003746

• Integrative Omics Analysis of Human Cartilage in Aging and Osteoarthritis

  This study investigates the tissue- and cell-type-specific genetic regulatory architecture of human knee joint tissues to elucidate the molecular underpinnings of osteoarthritis (OA). Matched cartilage, meniscus, and synovium samples were obtained from unrelated donors, comprising healthy organ donors with macroscopically normal cartilage and patients undergoing total knee arthroplasty (TKA) for severe OA. We performed whole-genome sequencing (WGS), bulk RNA sequencing of cartilage (n=113), meniscus (n=112), and synovium (n=81), and single-nucleus multiome (joint snATAC-seq + snRNA-seq) profiling on a subset of donors. By integrating these datasets, we performed cis-eQTL mapping in bulk and deconvolved cell-type-specific contexts across all three tissues, colocalization analysis with OA GWAS summary statistics (Regulatory Trait Concordance and coloc), rare variant promoter analysis, and chromatin-informed fine-mapping.In this updated version, the study has been expanded to a total of 220 unrelated donors. We added whole-genome sequencing (WGS) for 102 additional donors; small RNA sequencing (Illumina) of cartilage (n=92) and meniscus (n=88) to profile microRNA regulation; and long-read RNA sequencing (Oxford Nanopore PromethION P2) of cultured cartilage, meniscus, and synovium cells with and without interleukin-1β (IL-1β) stimulation (n=31) to capture full-length transcript isoforms of the inflammatory response.The data available through dbGaP include raw WGS sequence (FASTQ/CRAM), bulk RNA-seq sequence (FASTQ) from cartilage, meniscus, and synovium, small RNA-seq sequence (FASTQ), long-read RNA-seq (unaligned BAM), associated metadata, and donor phenotypic information.

  Study phs004730

• The Formation and Propagation of Human Robertsonian Chromosomes

  Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics have allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level will pave the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.

  Study phs003920

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

  We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.

  Study phs003406

• Heterogeneity in Lysosomal Storage Disorders

  Gaucher disease (GD) is an inherited lysosomal storage disorder caused by biallelic pathogenic variants in GBA1, which encodes glucocerebrosidase. Additionally, GBA1 variants are a well-established genetic risk factor for Parkinson's disease (PD), leading some PD research centers to incorporate GBA1 screening to identify patients who may benefit from targeted therapeutics. However, detecting GBA1 variants remains challenging due to the gene's high sequence homology with its pseudogene, which can give rise to complex recombinant alleles. This study evaluates the performance of Gauchian, a recently developed software tool for identifying GBA1 variants from whole genome sequencing (WGS) data. The assessment was conducted in a cohort of 90 individuals with GD and five GBA1 heterozygotes, all previously characterized through Sanger sequencing. While Gauchian successfully identified the most common genotypes, it demonstrated limitations in detecting rare or de novo variants due to its restricted internal database and heavy reliance on intergenic structural variants. These limitations led to misclassified homozygosity, incomplete genotyping, and undetected recombination events, ultimately reducing the tool's utility for comprehensive variant screening and precluding its application in diagnostic settings. The study dataset includes WGS from the 90 individuals used in the Gauchian pipeline. This data will be available through dbGaP to facilitate further research on GBA1 variant detection, genotype-phenotype correlations in GD and PD, and the development of improved bioinformatics tools for complex variant identification.

  Study phs003459

• Preclinical In Vitro Studies of Prenatal Treatment of Down Syndrome to Improve Brain Development and Neurocognition

  Down syndrome results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. There are no effective treatments for Down syndrome that improve brain development and neurocognition. Altered brain development occurs before birth in Down syndrome, which suggests that the optimal time to initiate therapeutic treatment is during prenatal development. In this study, neural progenitor cell (NPC) cultures were derived from induced pluripotent stem cells (iPSCs), to provide an in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the ability of pharmacological interventions to alleviate these effects. Gene expression was examined using bulk RNA-Seq in untreated T21 and euploid (control) NPCs and in NPCs treated with the candidate therapeutic molecules fasudil, apigenin, epigallocatechin-3-gallate (EGCG), isoxsuprine, and sphingosine. The results showed that the Rho-associated coiled-coil kinase (ROCK) inhibitor fasudil significantly downregulated expression of inflammatory pathway genes in T21 NPCs, of relevance because elevated inflammatory pathways are present in T21 and may contribute to deleterious phenotypes. Data available through dbGaP include five bulk RNA-Seq datasets from euploid and T21 NPC treated with the five molecules listed above, along with untreated euploid and T21 NPCs. Global protein expression data and phosphoproteomic profile data summary files, generated by tandem mass tag (TMT) mass spectrometry, are also available from untreated euploid and T21 iPSCs and NPCs.

  Study phs004455

• Kids First: Hear-'n-Seq Sequencing for Hearing

  One in 100 children will lose significant hearing by school age with hearing loss of 40 decibels or more, making hearing loss one of the single most common structural defects affecting the pediatric population. Hearing loss can affect a child's ability to develop speech, language, cognitive and social skills. The earlier a child with hearing loss starts receiving appropriate medical and educational services, the more likely they are to reach their full potential. More than half of early hearing loss is due to genetic factors. Approximately 1 in 500 babies is born with hearing loss. While the majority of prelingual hearing loss is nonsyndromic, over 400 syndromes have been described that have hearing impairment as a component. It is critically important to identify the etiology of hearing loss for many reasons, as there may be important health surveillance implications particularly with syndromic causes. Genetic testing is available for congenital hearing loss, but the current standard of care is by no means comprehensive because: 1) many types of genetic variants in known hearing loss genes are not detectable by clinical testing, and 2) it is estimated that more than 100 hearing loss genes are as yet unknown. With this proposal, called Hear-'n-SEQ, we will leverage the resources of the NIH Common Fund's Gabriella Miller Kids First Pediatric Research program to "seek-out" the genetic etiology of childhood hearing loss through comprehensive phenotypic and genomic analyses in an international cohort of hearing impaired patients. By sharing both the clinical and sequence data with the pediatric research community we will be empowered to identify genetic pathways that underlie hearing loss as well as pathways shared with other pediatric conditions. This project will be coordinated through the Harvard Medical School Center for Hereditary Deafness (HMSCHD). The Specific Aims of the project are to: (1) build an international consortium to identify and collect well-curated patient clinical information and DNA samples from children with hearing loss and their parents (trios) or carefully selected multiple affected individuals based on the pedigree structure, (2) submit appropriate DNA samples for whole genome sequencing at an NIH-supported sequencing center, and, (3) identify the genetic etiology of hearing impairment in individuals where possible, and integrate the data collectively into a shared data resource. Because of the tremendous genetic heterogeneity inherent in hearing loss, the proposed international collaboration will produce a maximum yield of diverse genetic causes, as it has been well established that different populations segregate distinct concentrations of hearing loss alleles. Therefore we will sample the hearing impaired pediatric populations of parts of Asia (Hong Kong), the Middle East (Turkey), and the US (individuals of European, African American, Central American and Caribbean descent). In addition to identifying novel etiologies for hearing loss, ultimately this work is designed to help create a pipeline for routinely integrating genomic sequencing into clinical diagnostics, generating more refined diagnostic capabilities, and ultimately more targeted therapies or interventions for children with hearing loss.

  Study phs002115

• The Genetic Landscape of Familial Pulmonary Fibrosis

  This dataset was collected from a study that was designed to identify disease-causing rare genetic variants in individuals with Familial Interstitial Pneumonia (FIP). Subjects were identified from our ongoing FIP Registry (IRB #020343), where FIP is defined as idiopathic interstitial lung disease (ILD) in two or more family members with at least one affected individual diagnosed with idiopathic pulmonary fibrosis (IPF). Whole exome sequencing was performed on ~600 affected members from 525 kindreds using genomic DNA isolated from peripheral blood.

  Study phs003750

• Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

  STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

  Study phs003511

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Prevent Pulmonary Fibrosis (PrePF)

  Cohort Description Prevent Pulmonary Fibrosis (PrePF) has been investigating the clinical, physiologic and genetic phenotypes of interstitial lung disease (ILD) by focusing on families with two or more cases of ILD and individuals with sporadic IPF. It has recruited over 1,200 families with two or more cases of pulmonary fibrosis. These families with pulmonary fibrosis include 2,837 individuals with probable or definite idiopathic interstitial pneumonia (IIP) and 2,404 unaffected FDRs. In addition, PrePF recruited over 10,000 individuals with sporadic idiopathic pulmonary fibrosis (IPF). Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 585 PrePF participants in C4R Wave 2 questionnaire data includes 448 variables for up to 370 PrePF participants in C4R Dried Blood Spot/Serosurvey data includes 7 variables for up to 206 PrePF participants in C4R Derived data includes 43 variables for up to 585 PrePF participants in C4R Phenotype data includes 113 variables for up to 585 PrePF participants in C4R

  Study phs002975

• The Effects of Long-Term Heavy Metal Exposure on Transcriptome Landscape in Human Peripheral Blood Cells

  The present study investigates the impact of long-term residence in a mining area on transcriptome changes induced by heavy metal exposure in human peripheral blood mononuclear cells (PBMCs) from 65 healthy subjects selected from the general population. This study includes the same participants which were recruited in our previous investigation on heavy metal long-term environmental exposure-related gene-specific methylation changes (phs003392.v1.p1). We performed a differential expression analysis to compare the mRNA transcriptome of 31 residents from the mining region (MRR) - individuals living in the Kapan mining area with reported environmental exposures to heavy metals - with that of 34 residents from non-mining regions (NMR) - individuals residing at a considerable distance from mining locations. We also evaluated the potential association of gene expression profiles with the blood metallome, including levels of Ca, Mg, Co, Fe, Mn, Cu, Mo, Se, Zn, As, Sb, Tl, Be, V, Ni. Poly-A selected strand-specific mRNA library was prepared with Illumina Stranded mRNA Prep kit. The sequencing was performed on the Illumina NovaSeq-6000 platform with 38.5 million single-end 100 bp reads on average generated per sample. Quality checking of the sequencing data was performed using Illumina Basespace reports and the program FastQC (V0.10.1). Reads were aligned against the Human Genome Hg38 using STAR (version 2.7.1a). According to our findings, long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. Pathway analysis revealed upregulation of immune response related pathways, and downregulation of translation and ribosome biogenesis in the PBMCs of the MRR. Pathways related to metal ion transmembrane transport, epigenetic modifications (histone deacetylases (HDACs) and DNA methylation) were upregulated in males, while in females mostly transcripts involved in inflammation and cytokine mediated signaling were upregulated. Additionally, among the dysregulated pathways, the TNF-α signaling via NF-κB showed opposite changes in females and males.

  Study phs003657

• Understanding Determinants of Racial Disparities in Lung Cancer Incidence

  This is a nested case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The study included 1258 cases and 1252 controls selected from the Southern Community Cohort Study (SCCS), a large, prospective observational cohort. Cases were identified from cancer registries across the catchment area of the SCCS. Cases and controls were frequency matched on age, sex, race, and enrollment site (community health center vs general population).

  Study phs003789

• Assessment of Epigenetic and Transcriptomic Signatures During Induced Neural Stem Cell Conversion of Human Blood Cells

  Cellular reprogramming by direct cell fate conversion has been shown to be associated with epigenetic de-aging. However, the dynamics of this process still remain elusive. Here, we generated induced neural stem cells (iNSCs) from erythroid progenitors of donors ranging from neonatal to 101 years of age by overexpression of the transcription factors SOX2 and MYC. First, performing DNA methylation analyses, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de-aging (data deposited as GSE295849). Studying the dynamic of epigenetic de-aging during iNSC conversion across time, we found that this process is largely protracted. Second, RNA sequencing analysis revealed that transcriptomic differences between young and old donor-derived iNSCs dissipate with extended time in conversion, too (data available through dbGaP). Concordant with this observation, established iNSC lines lack age-associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Finally, time course analyses on epigenome and transcriptome level both revealed that acquisition of a bona fide NSC signature extends greatly beyond the time point when proliferative PAX6-positive iNSCs emerge.

  Study phs004047

• Assessing Molecular GxT Interactions in Neural Progenitors Exposed to Valproic Acid and Lithium

  In this study we aimed to identify context-dependent regulatory functions of common genetic variation after stimulation with clinically relevant molecules, valproate and lithium. Fetal cortical tissue between 14 and 21 weeks gestation was subjected to RNA-Sequencing (232 samples) and ATAC-Sequencing (232 samples) to profile expression and chromatin accessibility, respectively. Considering donor genotypes, we were able to identify eQTLs, caQTLs, as well as response QTLs of both categories. The dataset provided here includes 232 RNA-sequencing files in bam format and 232 ATAC-sequencing files in bam format. We also provide 83 donor genotypes in VCF format (hg38). NOTE: Some sequence data files used in this study were previously submitted for phs003642.v1.p1 NIMH/Wnt_NeuralProgenitors. Investigators requesting access to data from phs004321 should also apply for access to phs003642.

  Study phs004321

• Integrating Contemporary Biospecimens and Immunomethylomics into the study of the Glioma Genetics and Immunity - CIDR

  Gliomas account for 80% of all malignant brain tumors and have an extremely poor prognosis, with a 5-year survival of 5.1%. The etiology of glioma remains poorly understood, with few established modifiable risk factors. Multiple studies have implicated infections in the development of glioma; however, the underlying mechanisms and putative causal pathogens remain unclear. In addition to risk, we have recently shown that reactivity to varicella zoster virus is also associated with a significant survival benefit in patients with glioma. Previous epidemiologic studies have investigated a limited number of pathogens using serological assays that only allowed detection. Recent analyses from our group have also highlighted that glioma subtypes have varying immune cells at diagnosis, and that there may be prognostic value. This CIDR proposal has two parts to add to the parent R01- Discovering Infection-mediated Pathways of Glioma Etiology and Prognosis by Leveraging Multiplex Serology and Immunogenomics (R01 CA266676) that applies multiplex serology and targeted HLA sequencing to understand the interplay between germline genetics, antigen reactivity and glioma risk/survival. In the first part of this application, we seek to expand our current plans to include 447 Immune Profiles Study subjects that have contemporary treatment, and highly detailed longitudinal biospecimens and clinical data measured at every clinic visit across the course of treatment. We plan to genotype these subjects for inclusion in viral antigen measurement and HLA sequencing. We will also include 30 cross-study replicate samples from the UCSF Adult Glioma Study (dbGaP Study Accession: phs001497) in this genotyping project. The second part of this CIDR proposal seeks to analyze whole blood methylation to deconvolute blood cell proportions for 1592 glioma cases and 1147 matched controls from the Adult Glioma Study that do not have existing blood methylation. The derived blood cell proportions will facilitate a deeper understand of the subtype specific risk and prognosis associated with immune cell traits, integrate mediation by germline genetics, and hone the antigen associations by controlling for antigen presenting cells. This proposal will unite two parallel, but independent and complementary studies, and will complete the viral, immunologic and genetic understanding of the association with viral reactivity and immune cells that will pave the way for functional studies. This will allow us to develop comprehensive immunogenomic models for predicting glioma risk and survival. Taken together, the proposed study will contribute new, high-quality data that will significantly advance our understanding of glioma pathogenesis, as well as inform avenues for prevention and improvement of outcomes in glioma patients.

  Study phs003990

• Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

  This study of primary human pancreatic ductal adenocarcinoma (PDAC) tumors (n=62) aims to characterize intratumoral clonal diversity, transcriptional plasticity, tumor–microenvironment interactions, and spatial patterns associated with progression and metastasis. Combined single-cell RNA sequencing and spatial transcriptomics enabled reconstruction of tumor phylogenies and mapping of clone-specific transcriptional states. Extensive intratumoral heterogeneity was observed, with multiple genetically distinct neoplastic clones coexisting within tumors. Distinct clones exhibited unique interactions with stromal and immune cells, and dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) programs and immune-suppressive microenvironments correlated with metastatic potential and lymph node colonization. A recurrent classical-to-basal clonal transition associated with MYC amplification and reduced immune response was identified and experimentally validated, implicating clonal evolution in emergence of more aggressive phenotypes. Controlled-access dbGaP deposits will include raw sequencing data from single-cell RNA sequencing and spatial transcriptomics experiments and de-identified clinical/sample metadata.

  Study phs004079

• The Genetics of Obesity, Diabetes, and Heart Disease in African Diaspora Populations

  African Americans have one of the highest rates of type 2 diabetes in the United States, and often have other medical problems related to obesity and cardiovascular disease. These conditions have various risk factors, including high blood sugar levels, high cholesterol levels, and insulin resistance. However, these risk factors need further study in individuals with African ancestry, including Afro-Caribbean and sub-Saharan Africa migrant populations. Genetic study of obesity, adult-onset diabetes, heart disease, and other common health conditions in African ancestry individuals across the Diaspora could be particularly informative. Therefore, this study is designed to collect genetic and non-genetic information from individuals with African ancestry to study common health conditions related to obesity, adult-onset diabetes, and heart disease. This ongoing study includes individuals at least 18 years of age who self-identify as African American, Afro-Caribbean, or migrants from sub Saharan Africa. Participants undergo physical examination and provide a blood sample for study. Participants also answer questions about personal and family medical history and current lifestyle behaviors. No treatment is provided as part of this protocol.

  Study phs004382

• Multi-omic Characterization of Genetic Variants in IBD Risk Loci

  This study aims to identify potential target genes of GWAS loci for inflammatory bowel diseases (IBD) by mapping expression quantitative trait loci (eQTL) using colon tissue from a cohort of 252 IBD patients. Results were compared to non-IBD colon eQTL from GTEx and BarcUVa-seq (GTEx Consortium, Science 2020 / Díez-Obrero V et al., Cell Mol Gastroenterol Hepatol. 2021). Statistical colocalization of eQTL and GWAS loci revealed novel colocalizations and target genes using diseased tissue. These eQTL also had regulatory and functional characteristics which were distinct from non-IBD eQTL. Available data includes typed and imputed genotypes, raw total RNA-seq, and association results.

  Study phs003881

• The National Myelodysplastic Syndromes (MDS) Study- Digital Histopathological Slide Images

  The goal of the National MDS Study was to establish a publicly available resource to facilitate the study of MDS natural history. This was accomplished through: 1) Creation of a multi-institutional, rich clinical database with genetic sequencing, longitudinal biorepository of consistently processed and clinically well-annotated blood and tissue specimens collected prospectively from participants with MDS and participants with idiopathic cytopenia of undetermined significance (ICUS); and 2) Support for investigator-initiated studies of MDS that will have high-impact for MDS patients, including basic science, clinical, health outcomes and epidemiological research. The study has assembled a comprehensive worldclass clinical database from over 2,100 participants with suspected or newly diagnosed MDS or MDS/MPN overlap disorders including extensive quality of life assessments, laboratory data, exposure history, histopathology slides and images, targeted and whole genome sequencing data, and hematopoietic and germline tissues representing high-quality biospecimens and data from diverse centers across the United States. These resources are now made available to the scientific community to support investigator-initiated research. The Digital Histopathological Slide Image data set further enhances the characterization of the MDS study cohort. The image library contains a total of 3,988 digital histopathology slides (H&E and Wright stained) of bone marrow aspirate and biopsy samples as well as peripheral blood smears collected from 1,652 MDS participants at baseline and follow-up visits. Clinical data associated with these images includes basic demographics, the central pathologist's WHO classification, and other slide review comments. Additional characterization of the MDS participants is available for further evaluation. The slide image library provides an extensive and unique resource to the research community offering a platform to evaluate new techniques that could potentially lead to improvements in diagnostic screening procedures and classification of patients with MDS.

  Study phs004357

• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

  Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

  Study phs003641

• Retinal Contributions to Vision Loss in Albinism

  The human fovea supports some of our most important visual functions, such as color discrimination and high acuity vision, but there remain significant gaps in our understanding of foveal development and the exact causal relationships between structural pathology and specific visual deficits. This study employs human albinism (a hereditary condition in which the fovea is grossly underdeveloped) as a natural model to examine these and other key issues. Using advanced non-invasive imaging approaches together with genetic testing, we seek to reveal the physiological and anatomical basis for visual deficits in albinism on a personalized basis and to refine the anatomical outcome measures for use in correlative studies and emerging therapeutic trials in albinism. Specifically, given the central role of the fovea in our visual function, this study seeks to elucidate the genetic factors affecting normal foveal development, to advance our understanding of a wide range of conditions associated with altered foveal morphology. Around 300 people will be recruited for this study, with an anticipated ~250 consenting to sharing their data in dbGaP. Next generation sequencing of participant samples will be done to analyze over 100 genes (list below) with links to albinism. Information collected for each sample for inclusion in this study will include: Sequencing-derived raw genetic data of study participants,Demographic data, including age, sex, race, Hispanic ethnicity, and gender identity (in some cases)Albinism phenotypeOther related phenotypic data if/when collected: premature birth, AOSLO retinal imaging, ancillary retinal imaging, visual field & fixation evaluation, color vision testing, and macular pigment optical densityClinical data when possible/available, such as: stereoacuity, BCVA, foveal pit morphology, NIR autofluorescence signal

  Study phs003573

• A Case Controlled Etiologic Study of Sarcoidosis (ACCESS-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 (ACCESS) include Bronchial Lavage, DNA, Peripheral Blood Mononuclear Cells, and Plasma. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine the etiology of sarcoidosis by establishing a case control, multi-center study. In addition to etiology, this study also sought to examine socioeconomic variables and the clinical course of patients with sarcoidosis, including quality of life.Background: Sarcoidosis is a chronic granulomatous disorder of unknown cause that is characterized by activation of T-lymphocytes and macrophages. For many years, sarcoidosis was presumed to be an atypical manifestation of tuberculosis because of the similarity between the inflammatory responses of the two diseases. However, as culture techniques became more widely employed to diagnose tuberculosis and it became less common, it became clear that sarcoidosis was not simply a variation of tuberculosis. Data on the etiology of sarcoidosis have come from diverse sources: in clinical investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. The cause may not prove to be a single, known exposure. Interactions of exposures with genetic dispositions could have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis.Participants: 736 participants with sarcoidosis enrolled within 6 months of diagnosis from 10 clinical centers in the U.S. Using the ACCESS sarcoidosis assessment system, organ involvement was determined for the whole group and for subgroups differentiated by sex, race, and age (Conclusions: The initial presentation of sarcoidosis is related to sex, race and age, and it tends to remain stable over two years in the majority of patients. The etiology is probably multifactoral with both genetic and environmental factors contributing.Specimen Details: The PBMC for this study are pelleted and suspended in guanidinium-based solution and are nonviable.

  Study phs004276

• The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository): Motor Neuron/Amyotrophic Lateral Sclerosis (ALS) Study

  The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository), banks phenotypic data and biological samples, including from individuals with motor neuron disease, in order to facilitate gene discovery in neurological disorders. Those samples are used in a number of studies, and genotyping data from studies using this resource are encouraged to be shared via dbGaP. Many studies have already shared data in this fashion, which in turn, can be linked back to the biologicals banked at the NINDS Repository. Motor Neuron Disease is characterized by selective degeneration of the motor neurons of the spinal cord, brainstem, or motor cortex. Clinical subtypes are distinguished by the major site of degeneration. In Amyotrophic Lateral Sclerosis (ALS), there is involvement of upper, lower, and brainstem motor neurons. In progressive muscular atrophy and related syndromes, the motor neurons in the spinal cord are primarily affected. With progressive bulbar palsy, the initial degeneration occurs in the brainstem. In primary lateral sclerosis, the cortical neurons are affected in isolation (Adams et al, Principles of Neurology, 6th ed, p 1089). The Motor Neuron Disease Collection of DNA and cell lines in the NINDS Repository is largely Amyotrophic Lateral Sclerosis cases (others include progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, Kennedy's disease). Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). Although ALS is the most common MND, it is still a relatively rare disease with an incidence of around 1.6 per 100,000 in the United States. It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered (including SOD1). However, most forms of the disease are not obviously familial. It is suspected that the sporadic forms of neurodegenerative disorders are caused by multiple genetic variants that individually make relatively weak contributions to risk. There is also an associated Control collection (see dbGaP and Coriell). Studies in motor Neuron Disease may use cases from the NINDS repository, controls from the NINDS repository, as well as cases, and controls, from other sources. A subset of subjects from The National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center: DNA and Cell Line Repository (the NINDS Repository): Motor Neuron/Amyotrophic Lateral Sclerosis (ALS) Study was utilized in the Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data study. Note: The publication Chio et al., 2009 states that "Raw sample-level genotype data from the initial GWAS study ... are available for download through the dbGAP portal (phs000006.v1.p1)". Instead, please follow this link: phs000101.v1.p1.

  Study phs000006

• Substance Use and Immunity in HIV+ Adolescents by Systems Biology

  Marijuana contains a complex variety of unique cannabinoids, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), known to impact inflammatory and lymphocyte activation pathways in the lymphoid tissues and brain. While marijuana continues to be classified under United States federal law as an illegal drug, medical use of cannabis is legal in at least 35 states, including 16 states and the District of Columbia where recreational marijuana is approved for individuals over the age of 21. In many states HIV infection is the sole indication for the use of medicinal marijuana as adjuvant therapy. Cannabis is effective in the treatment of HIV-associated peripheral neuropathy, improves appetite, and enhances overall quality of life of people with HIV while the anti-inflammatory effects of cannabis may improve HIV-associated complications. However, few studies have examined the effect of recreational or medicinal cannabis use on inflammatory pathways in peripheral blood cells among individuals with HIV. The goal for this study is to assess the anti-inflammatory effect of recreational marijuana use by YWH. Using a systems biology approach, unique genetic and cellular pathways within the peripheral blood cell transcriptome in a population of virally suppressed YWH on ART who used marijuana, alone or in combination with tobacco, compared to a reference group of youth without HIV.

  Study phs002090

• The Electronic Medical Records and GEnomics Network Genomic Risk Assessment (eMERGE IV)

  The eMERGE (electronic MEdical Records and GEnomics) network enrolled ~25,000 individuals not typically involved in research in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report along with recommended actions. The GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports and was returned to participants, their providers, and their EHR. The network is examining the uptake of care recommendations after return of results.Children's Hospital of Philadelphia (CHOP)The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP) with the primary goal of translating basic research findings to medical innovations. The mission of CAG is to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders. We aim to discover genetic causes for the most prevalent diseases of childhood including ADHD, asthma, autism, diabetes, epilepsy, obesity, schizophrenia, pediatric cancer, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Our participants are recruited from the CHOP Health Care Network, which includes over 50 sites throughout Pennsylvania and New Jersey, 100% of which use Epic EMR system. This constitutes the country's largest pediatric integrated delivery system, supporting >1.1 million visits/year within the primary and specialty care networks, community-based inpatient pediatric and neonatal programs, a rehabilitation hospital, and a home care service. It provides acute- and well-care to patients in urban, rural, and suburban settings.Cincinnati Children's Hospital Medical Center (CCHMC)CCHMC has proposed ambitious initiatives for eMERGE IV. The major goals are to generate, return as appropriate along with clinical recommendations, individualized genomic risk assessments that include polygenic risk scores for 2500 minority participants ascertained on dyads (mother/child) and extended to families (dyad + biologic father, siblings). The informatics initiatives include integration of electronic medical records and development, implementation and evaluation of clinical decision support at two different hospital systems, one pediatric and one adult. Participant preferences, education needs, and ethical and social implications will be studied throughout the 5 year period. Columbia UniversityColumbia University in partnership with the New York-Presbyterian hospital has a long and strong tradition of patient-centered research and community engagement in the urban, medically underserved communities of Washington Heights and Harlem in Northern Manhattan, and has established Precision Medicine as a major university-wide initiative (PMI), of which eMERGE is a vital program. We possess broad and deep expertise in clinical genetics, genomics, informatics, EHR phenotyping, systems biology, public health, and ELSI, including return of genetic results and secondary findings to diverse patients. Columbia will share lessons learned in linking EHR and sequence data for genomic decision support, developing scalable genomic education methods and assessing the impact of returning genetic results on patients, families, and clinicians. We are poised to contribute novel comprehensive risk prediction and management solutions for diverse patients as part of eMERGE IV efforts.Icahn School of Medicine at Mt. Sinai (Mt. Sinai)Mt. Sinai investigators have been at the center of many NHGRI-led genomic research (GSP, PAGE) and genomic medicine (eMERGE, CSER, IGNITE) consortia. Building on our decade-long track record in genomic research, clinical trials, and genomic medicine in diverse, underserved patients from New York City, we propose to develop new frameworks to bring genomic risk into clinical care to promote health equity. In addition to genomic discovery and risk prediction, we are creating analytical and data resources, and digital health applications tailored to diverse populations, as part of the eMERGE IV Network. The Mt. Sinai team is composed of clinicians and scientists who work closely with community members and industry partners to develop flexible and innovative strategies to bring leading-edge research into clinical care. Having recently announced a large institutional investment to scale the integration of genomics and artificial intelligence into patient care, Mt. Sinai is poised to contribute to eMERGE IV's mission to implement and learn from genomic risk assessment in clinical care. Mt. Sinai's team will contribute to progress in multiple areas across eMERGE, including developing and deploying electronic phenotypes; discovering new genotype-phenotype associations; and facilitating the communication of genomic results to patients and their healthcare providers.Mass General BrighamThe eMERGE IV Clinical Center at Mass General Brigham leverages a large biobank, clinical data in the electronic health records (EHR) for >6 million patients from the largest integrated health care provider in New England, advanced bioinformatics expertise, prior leadership in PRS development, established expertise in returning genomics results, and experience using information technology to transform clinical processes and assess medical, behavioral and economic outcomes. We have developed highly specific machine learning algorithms for e-phenotypes and implemented eMERGE algorithms for multiple phenotypes and have considerable experience in developing decision support tools and analyzing outcomes that can be leveraged to study the integration of PRS data into clinical practice. We will test the hypothesis that PRS will allow us to stratify eMERGE participants based on genetic risk for common complex traits. We will focus on coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer and depression in GWAS populations and validate multi-ethnic PRS in the Mass General Brigham Biobank and eMERGE III dataset. We will conduct an analysis of the effect of disclosing results to high risk participants to determine how personalized results changed patient outcomes in laboratory values, risk reduction behaviors, or health care utilization.Mayo Clinic (Mayo)The goal of Mayo eMERGE investigators is to leverage the electronic health record (EHR) for genomic discovery and to implement genomic medicine to improve health care outcomes, working closely with other eMERGE sites and the Mayo Center for Individualized Medicine. In eMERGE I we used genotype data and electronic phenotyping algorithms for genomic discovery. In eMERGE II we conducted a clinical trial of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD) and placed pharmacogenomic variants in the EHR with linkage to clinical decision support (CDS). In eMERGE III, we returned actionable findings from targeted sequencing of 68 genes and collaborated with a Federally Qualified Health Center (FQHC) to bring genomic medicine to an under-represented population. In eMERGE IV, as part of the Genomic Risk Assessment & Management Network, we will test the hypothesis that individuals at high polygenic risk for common diseases will have a higher uptake of risk reduction measures than those at lower risk. We will build on our prior work in genomic discovery, EHR integration and return of results (RoR) to develop and validate PRS and combine these with clinical risk scores and family history to compute comprehensive risk profiles for 2500 individuals. Our prior work in disclosing a PRS for CHD to research participants as part of a comprehensive risk profile enables us to efficiently expand the approach to other common diseases that pose a significant public health burden. To assess the utility of PRSs, we will recruit 1800 adults and 200 adolescents from Rochester MN and 500 adults from Phoenix AZ. DNA will be sent for CLIA-certified genomic testing and we will calculate ancestry specific PRSs for each participant. Individualized risk estimates will be reported to participants and health care providers (HCPs) and placed in the EHR with linkage to CDS that includes guideline-based risk-management information. For participants who are at significantly higher polygenic risk of developing at least 1 of the diseases, results will be disclosed in-person by a HCP followed by assessment of outcomes including new tests ordered, risk reduction measures, and changes in modifiable risk factors. We will examine the economic, behavioral and psychosocial implications of returning PRS. Our focus on PRS for common cardiovascular diseases brings genomic medicine to the population. We will continue our partnership with Mountain Park Health Center, a FQHC serving low-income, minority communities in Phoenix AZ, to address concerns about health disparities in the context of genomic medicine.Northwestern University (NU)Northwestern University is dedicated to translational genomics, with a strong focus on unified, interdisciplinary research bridging the informatics, clinical, basic science, and bioethics domains. Over the phases of eMERGE, Northwestern has applied this interdisciplinary approach to study the feasibility, utility, outcomes, and effectiveness of EHR-linked genomic information as a member of the network. Particular areas of focus include: novel informatics approaches to integrate genomic results into EHR systems; development of open-source, EHR-based phenotyping algorithms to empower translational research across a variety of clinical domains; and studies of participant, patient, and provider interaction with EHR-based genomic results. In phase IV of eMERGE, Northwestern is building on this expertise to develop, deploy, and evaluate systems of EHR-based, genomics-guided clinical risk assessment and management tools across a variety of common, impactful conditions. Northwestern's cross-disciplinary approach to this work is empowered by an innovative smartphone app to consolidate outreach, enrollment, engagement, return of results, and dissemination of health education materials surrounding genetic risk and risk management. Focusing recruitment on community-based clinics, Northwestern aims to engage participants from communities that, though not traditionally included in academic research settings, could benefit significantly from these risk management approaches. By combining expertise in informatics and EHR integration with innovative return-of-results strategies rooted in behavior theory, Northwestern aims to provide valuable data on accuracy, utility, and uptake of genetic risk assessment as the field moves towards integrating genetic risk scores into clinical practice.University of Alabama at Birmingham (UAB)Our eMERGE team aims to bring our experience and expertise in research with medically underserved (>75%) populations to identify genomic signatures of common diseases, conduct genomic risk assessments within the clinical workflow and where appropriate, pre-treat at-risk patients with common diseases including diabetes, chronic obstructive pulmonary disease, obesity, coronary artery disease and prostate cancer. Our aims will also allow us to develop genomic risk assessments, and address challenges involved in bringing genomic medicine into routine medical care. Working with the eMERGE network, we will select the eleven diseases of public health impact and select polygenic risk scores for clinical implementation. We will conduct an ethical legal social implications (ELSI) study, to explore patient perspectives on the use of family history and polygenic risk scores for estimating disease risk among Alabama Genomic Health Initiative (a statewide cohort) participants. The results will inform the development of consent, educational materials, and a communication strategy to enhance recruitment and retention of eMERGE participants. Recruiting over 75% of patients from medically underserved communities, we will incorporate genomic risk, family history, and clinical data to identify high-risk patients, recommending risk reduction recommendations in concordance with practice guidelines. For high-risk patients, we will deploy clinical decision support and present the genomic risk assessments and risk reduction recommendations. We will assess three outcomes: uptake of recommendations (implementation outcome), adherence to clinic visits (engagement outcome), and surrogates of disease/control (clinical outcome; e.g. blood sugar, cholesterol). We bring our expertise and experience to collaborate with the eMERGE investigative team to leverage the power of genomics to prevent disease.University of Washington (UW)The eMERGE IV Northwest partnership includes clinicians, scientists, and professionals in other fields from University of Washington (UW) Medicine, UW Health Sciences, the Fred Hutchinson Cancer Research Center, and the Brotman Baty Institute for Precision Medicine. The eMERGE IV Northwest partnership aims to evaluate the use of genomic information in the health care of diverse participants at the University of UW. Our site is expected to lead work on the prediction of colon cancer, glaucoma, and cardiovascular disease; other conditions expected to be studied include diabetes, liver disease, high cholesterol, and osteoporosis. Working with our eMERGE colleagues, we will aggregate, into a single score that informs about the risk of a disease, a participant's polygenic test information, which looks at variants from across the genome, as well as other known risk factors, such as personal and family medical history, environmental and social determinants, and physical and lab results. This score would let clinicians know which patients might benefit from screenings or other interventions to reduce the risk of disease or make an early diagnosis. In addition to experts specializing in each of the medical conditions that are the focus of the Northwest site, leaders in health economics, and in the ethical and societal aspects of genomics and health care will also be part of the research team. Medical, as well as economic, outcomes will be measured. Stakeholder engagement will be encouraged to obtain comments from participants and their families.Vanderbilt University Medical Center (VUMC)Vanderbilt University Medical Center has embraced Personalized Health and Healthcare as a key pillar of our Research Strategic Plan. This institutional commitment has taken multiple forms including the development of key infrastructure resources (the institutional Biobank (BioVU); the program in preemptive pharmacogenetic testing; the genotyping and sequencing core) and support of faculty in key disciplines such as genomics, informatics, ethics, privacy science, and clinical pharmacology. VUMC's team has contributed importantly to progress in multiple areas across eMERGE, including developing and deploying phenotype algorithms; developing and managing the genotype quality control pipeline for the network (eMERGE I); discovering new genotype-phenotype relations in VUMC and cross-network datasets; actively participating in the PGx clinical implementation project, community consultation, and return of results initiatives; developing methods to resolve tensions between data access and individual privacy; developing sampling methodology for the CERC survey; and developing new software tools for the field, including for developing and validating phenotypes, de-identification and for the phenome-wide association study paradigm (“PheWAS”)eMERGE Network Coordinating Center (CC)Vanderbilt University Medical Center has been the coordinating center of the eMERGE Network since inception. During this phase of eMERGE we have partnered with the Broad Institute to to add expertise in large-scale genotyping, cloud computing, and genomic data analysis and management, and with Duke University to leverage its proficiency in the implementation of patient-oriented family history tools and delivery of risk assessments. To meet the needs of the Network, the CC continues to serve NHGRI, the Network, and its members in all coordination, communication, and collaboration functions while providing a nationally visible home for eMERGE authored tools and scientific productivity. The CC is also assisting the Network with selecting and validating polygenic risk scores (PRS) for approximately eleven complex diseases and developing genomic risk assessments (GRAs) which combine the PRS with other clinical risks, family history, and monogenic risks. Finally, The CC will coordinate a prospective study for 25,000 participants which calculates clinical and genomic risks for participants and their providers. In addition to providing the genotyping and PRS reporting services, we will develop with the Network scalable EHR-based methods to assess uptake of risk-reduction recommendations and clinical impact.

  Study phs003905

• RNA Transcriptomic and DNA Methylation Landscape in FTLD-TDP and Controls

  Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia in individuals younger than 65 years, with the aggregation of TDP-43 as one of the most common forms of FTLD. FTLD-TDP is clinically, genetically and pathologically heterogeneous, with GRN and C9orf72 as the most common genetic forms (although more than 50% of the cases are genetically unexplained), and A, B and C as the most common pathological subtypes. To investigate the molecular differences between the different forms of FTLD-TDP, we performed bulk RNA sequencing (RNAseq) and reduced representation bisulfite sequencing (RRBS) from different brain regions of FTLD-TDP patients and controls. The RNAseq dataset includes samples from the frontal cortex of 149 individuals, comprising 127 FTLD-TDP cases (genetically unexplained types A (27), B (20) and C (22), 24 GRN mutation carriers, and 34 C9orf72 expansion carriers) and 22 controls. The RRBS dataset includes samples from the frontal cortex of 158 individuals —119 FTLD-TDP cases (genetically unexplained types A (25), B (24), and C (25), 20 GRN mutation carriers, and 25 C9orf72 expansion carriers) and 39 controls; and from the cerebellum of 151 individuals —113 FTLD-TDP cases (genetically unexplained types A (24), B (21), and C (23), 20 GRN mutation carriers, and 25 C9orf72 expansion carriers) and 38 controls. In total, the study consists of data from 183 unique individuals, with some overlap across the different datasets.

  Study phs004075

• Genetic Testing to Understand and Address Renal Disease Disparities across the United States (GUARDD-US)

  GUARDD-US is a prospective, multicenter, unblinded, two arm randomized pragmatic clinical trial. Participants will be randomized in a 1:1 ratio to immediate APOL1 gene testing and return of results (ROR) to participant and provider (Intervention arm) versus delayed APOL1 gene testing and ROR to participant and provider (Control arm). The main study will compare outcomes between APOL1 positive participants in the Intervention arm (i.e., early knowledge of APOL1 status) to APOL1 positive participants in the Control arm (i.e., delayed knowledge of APOL1 status). Participants that are APOL1 negative in the Intervention and Control groups will not be included in the main study analyses.Approximately 6,750 participants of African ancestry, age 18-70, with hypertension that either: 1) do not have diabetes and do not have CKD, or 2) have CKD (with or without diabetes) were randomized for the GUARDD-US study. GUARDD-US also includes a substudy to determine the effect of knowledge of genetic test results that predict efficacy of various antihypertensive medications on change in SBP from baseline to 3 months in APOL1 negative individuals at participating sites. The population for the PGx substudy were participants from main study (above) who were randomized to Intervention and who test negative for APOL1. Only participants from PGx substudy participating sites were included in this population.

  Study phs004045

• Virginia PrIMeD Study

  The goal of this study was to determine whether screening children (2-16 yrs) in pediatric waiting rooms for genetic risk of type 1 diabetes (T1D) could be applied to diverse (by geography, genetic ancestry) communities, and for those at "high genetic risk," if barriers prevent subsequent screening for presence of islet autoantibodies. A total of 3,818 children were recruited from eight general pediatric and specialty clinics across Virginia. Clinical Research Coordinators were stationed at each clinic and obtained informed consent/assent, a brief medical history, and a saliva sample for DNA extraction and determination of their genetic risk using a T1D Genetic Risk Score (T1D GRS). Children were present in the clinic for a "healthy" visit, although children with and without a history of T1D were recruited into the study. Age, sex, self-reported ancestry/race, T1D history, and other medical history information was obtained. DNA was extracted from the saliva samples and genotyping with a T1D-focused array using 74 SNPs (including 26 SNPs in the HLA region) provided data to generate a T1D GRS for each individual. Of the 3,818 children recruited, there was a slight excess of males (1,959, 51.3%), a majority of white and Hispanic/Latino ancestry (82.8%), and 91 (2.4%) with prevalent T1D. A total of 542 (14.2%) had "high T1D genetic risk" (T1D GRS > 5). Although the T1D GRS included non-HLA genetic variants, 80% of those with "high genetic risk" would have been classified using only those SNPs in the HLA region alone. Of children with "high genetic risk" and without pre-existing T1D (n=494), 7.0% (34/494) consented for islet autoantibody screening. Among children with pre-existing T1D (n=91), 52% (n=48) also had a "high genetic risk." The HLA-focused T1D GRS was not significantly associated with age at onset of T1D. Of those at high genetic risk that consented for autoantibody testing (n=34) and completed the blood collection (n=28), two (2/28, 7.1%) tested positive for multiple autoantibodies and were at significant risk of developing T1D. Follow up of 55% of parents/guardians identified 2 (of 2,096, 0.095%) participants who developed T1D, one at "high genetic risk" and one with a first-degree relative with T1D. A major factor in obtaining islet autoantibody testing was concern over SARS-Cov-2 exposure and an independent non-scheduled blood collection.Individual-level data at each SNP (genotyped and imputed) for T1D genetic risk and affiliated data are provided in dbGaP.

  Study phs003609

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Network - Functional, Imaging, and Respiratory Evaluation in CORAL (PETAL FIRE CORAL-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 PETAL FIRE CORAL include plasma and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent and biospecimens may not be used to produce commercial products.Objectives: To examine the recovery from COVID-19 disease following acute hospitalization with an emphasis on functional, imaging, and respiratory evaluation, and assess the feasibility of conducting a larger study to evaluate variables associated with differential recovery.Background: The BLUE CORAL study, dbGaP phs003419, was intended to address the knowledge gaps and provide critical data to help guide clinical care, public health, and scientific efforts regarding SARS-CoV-2 (COVID-19) recovery. The understanding and treatment of long-term sequelae of COVID-19, referred to variously as post-acute sequelae of COVID-19 (PASC), post-acute COVID, long COVID, or long-haul COVID, is fundamental to patient recovery. These long-term consequences are common and increasingly recognized, although heterogeneous in manifestation, and can result in a failure to return to baseline level of health. At the time of the FIRE CORAL study, there were limited studies that collected objective assessments following hospital discharge for a wide spectrum of patients surviving COVID-19.Participants: FIRE CORAL enrolled adult participants as a subset of those enrolled in the BLUE CORAL study with a recent COVID-19 hospitalization and that completed the 1- or 3-month post-hospital telephone long-term outcomes assessment. The target enrollment for this pilot study cohort was 80 participants.Design: FIRE CORAL was a multicenter prospective cohort study of participants recovering from COVID-19 disease with in-person follow-up, as an extension of the BLUE CORAL study. The study consisted of a battery of assessments objectively measuring pulmonary function, abnormalities on lung imaging, and functional status. Participants were to attend and perform initial in-person testing at 3 to 9 months after hospital discharge. Participants with abnormal findings on pulmonary function testing or chest imaging during their initial assessment or those with persistent respiratory symptoms were eligible to repeat study procedures 3 months later with a subsequent visit at 12 months. All participants were invited to return for in-person follow up at 12 months after hospital discharge. Assessments included high-resolution chest CT scan without contrast, spirometry, lung volume assessment, diffusing capacity measured by single breath measurement, Six Minute Walk Test, Short Physical Performance Battery, St. George's Respiratory Questionnaire, and Functional Assessment of Chronic Illness Therapy-Fatigue scale. Demographic and hospitalization data are available as part of the BLUE CORAL study.The primary aim of the FIRE CORAL study was to examine the feasibility of conducting rigorous in-person follow-up testing of participants discharged from the hospital following COVID-19 illness to assist with planning for a larger study to evaluate variables associated with differential recovery. The secondary aim was to describe the pulmonary, imaging, and functional recovery following COVID-19 hospitalization in a diverse population of patients.

  Study phs004130

• HudsonAlpha Long Read Sequencing Data of Individuals with Rare Suspected Genetic Conditions

  The data included in this project were generated from several IRB projects focused on the identification of the underlying genetic cause of undiagnosed rare conditions in infants, children and adults enrolled across the southeastern United States. Long read genome sequencing was performed on DNA samples collected as part of an IRB-approved study and findings from this testing was returned to enrolled study participants and the clinical team providing care. Proband participants in these studies were enrolled in both inpatient (neonatal intensive care units) and outpatient settings. When possible, biological relatives (including both biological parents) were also enrolled to help clarify inheritance of variants identified. Sequencing and analysis for SouthSeq is conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Results of testing are disclosed to participants by genetic counselors or trained non-genetics providers who also facilitate sharing of results with the participants' medical care teams when appropriate. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within the current ACMG gene list.

  Study phs003537

• Germline Sequence Variation in Cancer Genes Among Rwandan Breast and Prostate Cancer Cases

  Inherited genetic information can reduce cancer risk and mortality using protocols for patient ascertainment, testing, counseling, prevention, and treatment. For example, carriers of germline BRCA1/BRCA2 or Lynch Syndrome mutations are at increased risk of breast, ovarian, prostate, endometrial, colorectal, and other cancers. Genetic testing is of clinical value because many mutations are actionable in reducing risk or determining appropriate treatment regimens. There is growing evidence that inherited genetic mutations represent a large proportion of cancer cases in sub-Saharan Africa (SSA). It is also well known that most cancer genetic testing data does not represent the racial and ethnic diversity of the US or global population. Despite the high proportion of cancer cases diagnosed at an early age and late stage, as well as the potential for interventions to reduce cancer risk and death by using genetic tools, genetic testing, counseling, and clinical management protocols have largely not been widely developed in SSA. In order to develop and evaluate the potential for genetic testing in SSA, we propose to undertake a proof of concept feasibility study of hereditary cancer that will contribute data on the prevalence of hereditary cancer mutations in SSA and inform the development of SSA-specific guidelines for cancer genetic testing. In this study, we undertook a pilot evaluation of research genetic testing and counseling in breast and prostate cancer cases in Rwanda that involved genetic testing of breast and prostate cancer cases.

  Study phs003927

• National Cancer Institute Multi-Ancestry Genome-Wide Association Study of Kidney Cancer (NCI-3)

  The National Cancer Institute (NCI) multi-ancestral genome-wide association study (GWAS) of kidney cancer ("NCI-3") was performed by NCI to further investigate common genetic variants associated with risk of kidney cancer and its two major subtypes across individuals of different ancestries (European, African, East Asian, Latin American). The NCI-3 GWAS includes 12,315 cases and 73,091 controls from 25 centers in North America, South America and Europe, genotyped using the Illumina Global Screening Array v2.0. SNP-level results from this GWAS were combined by meta-analysis with results from two earlier NCI European-ancestry GWAS (RCC; phs000351: 1,311 cases and 3,424 controls and phs001736: 2,417 cases and 4,391 controls), a NCI GWAS of African Americans (phs000863; 255 cases and 375 controls), GWAS conducted at other institutions [International Agency for Research on Cancer (scan 1: 2,438 cases and 5,071 controls; scan 2: 2,781 cases and 2,940 controls), The University of Texas MD Anderson Cancer Center (scan 1: 893 cases and 556 controls, scan 2: 1,241 cases and 1,712 controls) and the Institute for Cancer Research, UK (944 cases and 4,024 controls)] and GWAS analyses of data from three large biobanks (Biobank Japan: 523 cases and 86,306 controls; FinnGen: 2,095 cases and 304,956 controls; UK Biobank: 1,807 cases and 348,824 controls). Only individual-level data from NCI-3 and the two MD Anderson Cancer Center scans are included in this dbGaP submission. All study-specific and meta-analysis summary statistics are included.

  Study phs003505

• Genetic Analysis of Epidermal Inclusion Cysts

  The goal of this study was to identify a potential driver of epidermal inclusion cysts, or epidermoid cysts, (EICs) in human skin. Individuals were recruited at EIC excision appointments made a priori, with no exclusion criteria. Fresh biopsies and saliva were taken from consented patients, and DNA harvested immediately. Whole exome sequencing was performed (150-bp paired end reads) to 200X in tissue and 80X in saliva via Illumina NovaSeq 6000 sequencer. Identification of somatic mutations was performed using GATK best practices. Somatic variants in the NEK9 gene were found in 12/14 cases sequenced, with clustering of variants within the RCC1 and kinase domains of the protein.

  Study phs003776

• Multi-Ethnic Study of Atherosclerosis (MESA) - Cardiac CT Image Repository

  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 raw cardiac CT images. These new data are intended to be made available to interested researchers via BioData Catalyst, will include participants irrespective of participation in genetics (i.e. the full MESA cohort), and may be merged with currently posted (to dbGaP) phenotype and molecular datasets (WGS, GWA, RNA Seq, Methylation, Metabolomics, and Proteomics).

  Study phs004423

• Genome-Wide Association Study for Glucocorticoid-Induced Ocular Hypertension

  We aim to identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change utilizing genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. The primary outcome was IOP change from baseline to the maximum IOP measurement within 6 months of GC treatment. Study participants were derived from two cohorts: the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) clinical trial and Massachusetts Eye and Ear Infirmary and Retina Health Center (MEE/RHC) clinical sites. The discovery analysis was conducted using the FAME samples (GWAS: n=532, WES: n=534) and replication analysis was done using the MEE/RHC samples (GWAS: n=603, WES: n=601).IOP was measured at baseline and throughout the first 6 months of GC exposure. DNA samples were collected through blood and underwent genome-wide genotyping on Illumina's Global Screening Array (GSA) and WES using a custom exome bait from TWIST Biosciences on the Agilent Bravo automated platform. Rare variant gene burden analyses were applied across all ancestries and in the European subgroup after adjusting for covariates. Gene-level and pathway analyses were performed using MAGMA and expression/splicing quantitative trait loci (eQTL/sQTL) colocalization was completed using eCAVIAR.Demographic and phenotypic information of the 1166 participants enrolled are available in this dbGaP deposition, including information on the GC medications, IOP measurements within the 6 month follow up period, and ocular hypertension/glaucoma history. Array derived genotypes, genotype calls derived from sequencing, and whole exome sequencing data will also be available.

  Study phs004037

• Kids First: Whole Genome Sequencing Studies of Multiplex Nonsyndromic Cleft Lip/Palate Families

  Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that affects approximately 135,000 newborns worldwide, and imposes significant medical, psychosocial and financial burdens to affected individuals and their families. Genetic variation in numerous genes has been associated with NSCLP, however the exact mechanisms by which they contribute to the condition remain largely unknown. Here, we will use whole genome sequencing and robust analytical approaches to systematically evaluate the causes of NSCLP in 923 individuals from large multigenerational families.

  Study phs002626

• Incidental Detection of Maternal Neoplasia through Non-Invasive Cell-Free DNA Analysis (IDENTIFY), a Natural History Study

  Prenatal cell-free (cf) DNA sequencing for fetal aneuploidy incidentally detects circulating tumor DNA in the plasma of asymptomatic pregnant women. Distinguishing the subset of women with malignant tumors detected by prenatal sequencing from those with benign conditions, such as uterine fibroids, is critical to maternal medical management. The Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Sequencing (IDENTIFY) study at the National Institutes of Health in Bethesda, MD, offers standardized cancer screening and cfDNA sequencing to asymptomatic or minimally symptomatic pregnant women with nonreportable prenatal cfDNA sequencing results. We previously reported that whole-body magnetic resonance imaging (WB-MRI) and a specific genome-wide sequencing pattern of chromosomal gains and losses involving three or more chromosomes could reliably differentiate which women had cancer. We continue to explore additional noninvasive biomarkers to identify the subset of women with nonreportable prenatal cfDNA sequencing results who have cancer and to predict tissues of origin, particularly when patients or their providers are reluctant to pursue diagnostic testing, WB-MRI studies are unavailable, or imaging findings are indeterminate. Here, cfDNA sequence analysis was performed to identify cancer driver somatic mutations that might aid in distinguishing between pregnant women who have a high likelihood of occult malignancy from those who do not. In this pilot study, prospectively collected blood samples from 65 pregnant or postpartum women with and without occult cancers were analyzed blindly for cfDNA somatic mutations in 275 cancer-associated genes.

  Study phs004107

• Single Cell and Spatial Transcriptomics Studies of Fibrosis in Prospective Registry in IBD Study at MGH and GI Disease and Endoscopy Registry

  Stricturing disease or fibrosis is a common complication of inflammatory bowel disease (IBD), often requiring surgical intervention. This process is caused by the abnormal deposition of extracellular matrix in the context of inflammation, and thus involves crosstalk between multiple cell types including fibroblasts and immune cells. To understand the cellular interactions involved in fibrosis, we performed single cell and spatial transcriptomic analyses of biopsy or resection samples from IBD patients, diverticulitis patients or controls.For single cell analyses, intestinal samples were processed within three hours of collection by first stripping the epithelial layer with EDTA and then enzymatically digesting the underlying tissue. Cells from both the epithelial and tissue fractions were separately loaded in two channels on a 10x Chromium controller and libraries were generated with the 3'v3 Chemistry pipeline before sequencing on an Illumina sequencer. The resulting sequence data was demultiplexed and analyzed with the CellRanger pipeline to generate raw fastq files and processed gene-count matrices for each sample.For spatial transcriptomic analyses, intestinal resection samples were snap frozen in OCT (optimal cutting temperature embedding medium). Blocks were cut into 10μm sections in a cryostat and transferred to a 10x Genomics Visium slide v1. Spatially barcoded libraries were prepared according to manufacturer's instructions and sequencing on an Illumina sequencer. The resulting sequence data was processed with the SpaceRanger pipeline to generate fastq files and processed barcode-count matrices. Using the samples deposited here, we defined 68 fine-grained cell types across the ileum and colon of control and fibrotic intestinal tissues. We show that intestinal strictures were characterized by increased immune cells - including IgG+ plasma cells and CCR7hiCD4+ T cells - and inflammatory fibroblasts. We also define the transcriptional differences associated with fibrosis, with inflammatory fibroblasts in particular showing broad changes in gene expression. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Further, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.

  Study phs003943

• Non-Dependent Opioid Misusers as Controls for a Genome-Wide Association Study

  The Non-Dependent Opioid Misusers as GWAS Controls (i.e., the Opioid Misuse Study) is a genetic association study that was designed to compare adults with limited (6 months of daily or near daily) of opioid misuse. Participants were required to provide a source of DNA and to be of either non-Hispanic European American or African American ancestry (to yield adequately powered subsamples for genetic analyses). Adults (age >18 years) with a history of opioid misuse were recruited from Washington University School of Medicine (WUSM) recruitment and clinical sources, treatment centers, recovery residences, print and electronic advertisements, and social media. A brief, non-diagnostic screening call was completed to confirm the opioid misuse history of prospective participants. Limited lifetime misusers were required to have no opioid misuse for the past year. Extensive misusers were required to have had a clinical opioid use disorder diagnosis. Informed consent was obtained from all participants as per protocols approved by the institutional review boards of WUSM and the State of Missouri.A modified Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) obtained age of first, and most recent, use as well as DSM-5 substance use disorder diagnoses for heroin and prescription opioids (separately), cannabis, amphetamines, sedatives, cocaine, alcohol, and nicotine. Other assessed diagnoses included major depressive disorder, conduct disorder, and post-traumatic stress disorder. Non-diagnostic sections obtained information on demographics and suicidality. A short form version of the Addition Research Center Interview, added to assess the subjective effects of opioid misuse, was modified to enable retrospective assessment. A subsequent change to telephone interviews enabled recruitment of participants from a much broader geographic area encompassing the U.S. and Canada. Data are included here from 1774 individuals with a lifetime history of opioid misuse, of whom 1227 were of European American ancestry and 547 were of African American ancestry. We provide participants' estimated totals for number of times misused opioids lifetime and endorsement of opioid use disorder symptoms, which did not entirely correspond to our initial conceptualization of case and exposed control status.

  Study phs003684

• Integrative Analysis for Multi-Omics Data in Non-Small-Cell Lung Cancer

  We conducted epigenetic and transcriptomic mapping of primary non-small cell lung tumors and non-neoplastic tissues. 20 non-neoplastic lung tissues and 18 non-small cell lung tumors were obtained from Biorepository and Tissue Technology Shared Resource at Moores Cancer Center, UC San Diego. All tumor samples were in pathological stages I and II. 8 pairs of samples were "matched", meaning that the tumor and normal tissues came from the same patient. Microfluidic oscillatory washing–based chromatin immunoprecipitation followed by sequencing (MOWChIP-seq) was used to profile the binding of H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3. SmartSeq-2 was used to map mRNA expression. We identified a large number of differentially modified regions for both epigenetic and transcriptomic markers between tumors and normal tissues. Deep learning model showed extensive transcription factor network rewiring. Raw sequencing data of the ChIP-seq and RNA-seq libraries are available through this dbGaP submission.

  Study phs003113

• Chicago Infant Mortality Study

  The Chicago Infant Mortality Study (CIMS) was a population-based, prospective, case-control study conducted in metropolitan Chicago, Cook County, Illinois, to examine the risk factors for sudden infant death syndrome (SIDS) among a primarily Black population. Eligible case infants were aged birth to one year where the cause of death was determined to be SIDS while eligible control infants were aged one month to one year who died of other sudden unexpected infant death (SUID) causes. Recruitment occurred between November 1993 and April 1996. The goal of this ancillary multiomics study was to evaluate possible genetic and epigenetic determinates of SIDS and together with metabolomic profiles, identify novel clinical diagnostic tools to enable molecular autopsies and biomarkers to proactively identify and intervene in infants at greater risk of death from SIDS. The multiomics data was generated from medical examiner autopsy specimens and includes: whole exome sequencing genotypes; RNA-seq transcriptome and methylome profiles from autopsy heart tissue; and serum metabolomics profiles. The sample size available varies with the modality of the omics assay, but the total number of unique infants included is about 400.

  Study phs003790

• Kids First: Genomic Analysis of Pediatric Rhabdomyosarcoma

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the genomic and phenotypic data from this study are accessible through dbGaP. The data is also available at the Kids First Portal, where other Kids First datasets can also be accessed in the cloud for data analysis, data visualization, collaboration and interoperability, open to all researchers and developers. Rhabdomyosarcoma (RMS) is one of the most common and deadly sarcomas in children and adolescents, but very little is known about its genetic epidemiology. This study will explore the role of new (i.e., de novo) mutations in both known cancer predisposition genes and novel susceptibility genes on the risk of RMS. A better understanding of the genetic risks for RMS may lead to prevention strategies, better risk stratification, and even the identification of new therapeutic targets.

  Study phs004306

• Detecting and Subtyping Lung Cancer Through Analysis of Circulating Tumor DNA

  Small cell lung cancer (SCLC) is among the most aggressive tumors with poor clinical outcomes. Tumors are rarely resected, which is a major barrier to molecular profiling of tumor tissue; therefore, non-invasive approaches using circulating tumor DNA (ctDNA) from liquid biopsies are needed to help advance research and clinical care for patients with SCLC. We developed a targeted capture panel that profiles SCLC genes and transcriptional regulation sites, including transcription start sites (TSS) and transcription factor binding sites (TFBS). This is a single assay that detects genomic mutations and transcriptional regulation activity based on ctDNA fragment patterns reflecting epigenetic nucleosomal positions. We applied this assay to sequence patient-derived xenograft (PDX) and patient plasma samples. We also performed whole genome sequencing (WGS) for a subset of the PDX plasma samples to validate the capture data. We developed new algorithms to quantify activity of key SCLC marker genes of ASCL1, NEUROD1, POU2F3, and ATOH1 and to classify SCLC subtypes based on activity of these markers. Furthermore, we developed a model to classify SCLC from non-small cell lung cancer (NSCLC), which has potential important applications for monitoring transdifferentiation and tumor plasticity.

  Study phs003570

• Parkinson Cell Atlas in 5D (PD5D)

  Genome-wide association studies (GWAS) have unequivocally linked thousands of noncoding variants to Parkinson's disease (PD). Why have these breakthroughs not uncovered the mechanism(s) of common, genetically complex PD? We do not know how GWAS variants cause neurodegeneration, which variants are causal, and why they impair some brain cells but not others. Overwhelming evidence shows that cis regulation of transcription is the most likely mediator of disease risk, and that it is finely tuned by cellular and dynamic context.Here we will pinpoint the causal gene(s) through which GWAS loci function in spatially barcoded, single brain cells and, dynamically over pseudotime (Stage) using single-nucleus expression Quantitative Trait Locus (eQTL) analysis. Putative causal genes will be tested mechanistically in cell- and stage-specific analyses in vivo in Drosophila avatars and in vitro in human pluripotent stem cells. Moreover, we will identify the corresponding causal GWAS variants (eSNP) through allele-specific expression (ASE) and CRISPR/Cas9-variant editing in single brain cells. Our collaborative and highly integrated project will begin to reveal the complex human genetics of PD through a dynamic five-dimensional view of proximal cellular mechanisms across brain cells (1D), brain space (3D), and disease stage (1D).

  Study phs004421

• NCTN: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome (AAML1531)

  Study ID: AAML1531 NCT Number: NCT02521493 Children's Oncology Group (COG) Submitted in collaboration with the NCTN/NCORP Data Archive Trial Title: NCTN: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome (AAML1531) Trial Description: This phase III trial studies response-based chemotherapy in treating newly diagnosed acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome. Drugs used in chemotherapy 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. Response-based chemotherapy separates patients into different risk groups and treats them according to how they respond to the first course of treatment (Induction I). Response-based treatment may be effective in treating acute myeloid leukemia or myelodysplastic syndrome in younger patients with Down syndrome while reducing the side effects. Clinical data presented in the following publication(s): • PMID 34320162 Disease type(s): • Hematopoietic Neoplasm/Leukemia - Acute Myeloid Leukemia • Hematopoietic Neoplasm/Leukemia - Myelodysplastic Syndrome Clinical Dataset(s) included:• NCT02521493-D1 (PMID 34320162): There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D1 dataset is a patient level dataset (single row per patient) containing patient characteristics, laboratory findings (hemoglobin, peripheral WBC, peripheral platelet), cytogenetics, outcome (overall survival and event-free survival), neutrophil recovery, ICU admission, select toxicity data, and targeted sequencing data for eligible myeloid leukemia in children with Down syndrome (ML-DS) enrolled on the AAML1531 clinical trial. • NCT02521493-D2 (PMID 34320162): There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D2 dataset is an adverse event level dataset (single row per adverse event, period, and patient) containing information of the micro-organisms associated with adverse events by period in the AAML1531 clinical trial. Additional genomic data are available for this trial under phs002187.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 phs004081

• National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC-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 GenTAC include Aorta Tissue, Buffy Coat, DNA, EBV Cell Line, Lymphocytes, Plasma, and Polymorphonuclear Cells/RBC Pellets. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The overall objective of GenTAC was to establish a registry of patients with genetically induced thoracic aortic aneurysms and related cardiovascular conditions, and collect associated medical data, as well as blood and tissue samples and make them available to investigators to advance research in diagnosis and management of genetically induced thoracic aortic aneurysms.Background: Thoracic aortic aneurysms (TAAs) predispose individuals to life threatening aortic complications, including aortic dissection and rupture. The treatment of complications arising from TAAs is complex, with high rates of morbidity, mortality, and surgical procedures. TAAs are associated with loss of vascular smooth muscle cells and degeneration of extracellular matrix in the aortic wall. This degeneration may be caused by hypertension and inflammation, particularly in elderly individuals. Genetic mutations are the main cause of TAAs in many young or middle-aged individuals. Genetic disorders, such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome, have a high risk for TAA, and up to 20% of individuals with TAAs or dissection have a family history of TAAs without being affected by a known syndrome or known genetic mutation. While diagnostic and treatment advances have dramatically improved care for patients with genetically induced TAAs, many questions remain about how best to identify and treat these disorders. Thus, GenTAC was developed as a longitudinal registry for patients affected by genetically induced thoracic aortic conditions in order to facilitate ongoing and future investigations to improve the diagnosis and clinical management of patients with genetically induced TAAs. Information gained from studying the genetically induced TAAs is expected to benefit the clinical management of non-genetic TAAs, as well.Participants: Over 3,500 participants were enrolled.Design: GenTAC was a longitudinal observational cohort study of affected individuals with either known or suspected genetic mutation that predisposes them for thoracic aortic aneurysms and dissections (TAAD). There were no interventions planned, and all decisions regarding approaches to treatment were to be made by the patients and their care teams. Enrollment data were abstracted from medical records or obtained through patient interviews. The data collected include clinical evaluations (by several organ systems), historically diagnosed conditions and outcomes and drug treatment; patient reported quality of life, co-morbidities, family history, smoking, alcohol use, and pregnancy history; most recent imaging evaluations, genetic testing, blood chemistry, and surgical interventions. When blood could not be collected from participants, a saliva sample was obtained as a source of DNA. Excess aortic tissue was frozen from participants that underwent surgery. Follow-up data was collected at regular intervals for each participant enrolled, with the interval varying by the diagnosis. Follow-up data include outcomes, clinical and imaging evaluations and treatment and lifestyle changes since the enrollment visit. Images were read by the imaging core according to the study protocol. Diagnosis of each participant was confirmed by the phenotyping core.Conclusions: GenTAC established a vast biospecimen inventory and clinical database from over 3500 participants that is available to researchers with the ultimate goal of advancing the diagnosis and management of genetically induced thoracic aortic aneurysms and other cardiovascular complications. Some of the publications resulting from analysis of the GenTAC data and biospecimens can be found at https://www.nhlbi.nih.gov/research/resources/gentac/research.Publications: A list of GenTAC publications can be found on the GenTAC Alliance website: https://www.gentacalliance.org/publications/.

  Study phs004340

• Genome-Wide Association Study and Predictors of Neonatal Blood Cell Traits in Hispanic Newborns

  This study leverages cord blood samples from the NHLBI's Umbilical Cord Blood Unit Collection to conduct genome-wide association studies (GWAS) of neonatal blood cell traits in newborns of Hispanic ethnicity. Cord blood (CB) aliquots from 382 de-identified newborns of Hispanic ethnicity were obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) through Project Request #11595. The CB samples were originally collected between 1998-2001 as part of the COBLT (Cord Blood Transplantation) study. Briefly, the COBLT study primarily aimed to (i) build ethnically diverse public cord blood banks with standardized collection/processing protocols and (ii) to conduct a prospective phase II trial of unrelated cord-blood transplantation in pediatric and adult candidates for allogeneic hematopoietic stem cell transplantation. The collected CB units and aliquots are currently maintained by BioLINCC, with samples available from donors with diverse racial/ethnic background. All COBLT CB samples were red cell depleted, volume reduced and cryopreserved with DMSO/Dextran in 25 ml bags. Test aliquots were used by COBLT for flow cytometry to characterize predictors of time to engraftment for CB samples. Cell surface markers assessed included CD34, CD45, CD3, CD8, CD4, CD19, CD16, and CD56. CB aliquots were requested from subjects reported as Hispanic in the NHLBI Umbilical Cord Blood Unit Collection. Epidemiological data and cell-related indices were obtained from the Umbilical Cord Blood Unit Collection repository. To investigate genetic variation associated with blood cell traits measured in the Hispanic newborn samples, we isolated DNA from CB and conducted genome-wide SNP genotyping using the Axiom PangenomiX array (Thermo Fisher). Whole-genome imputation was performed using the TOPMed Imputation Server, and GWAS of 24 blood and immune cell traits were conducted in up to 382 Hispanic newborns for each trait.

  Study phs004758

• Health Effects of Arsenic Longitudinal Study

  The Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes. We applied array-based genotyping technologies to baseline DNA samples from a subset of the HEALS study and linked those genotypes to data on arsenic species measured in urine. We used these data to identify regions influencing arsenic metabolism (AS3MT and FTCD). We also applied array-based DNA methylation technologies to baseline DNA samples from a subset of individuals from HEALS. These data were linked to data on arsenic concentration (in both urine and drinking water) to identify regions of the genome where DNA methylation is impacted by arsenic exposure.

  Study phs003839

• Blood and Marrow Clinical Trials Network - A Multi-Center, Phase III, Randomized Trial of RIC, and Transplantation of (dUCB) Versus HLA-Haplo Related Bone Marrow for Patients with Hematologic Malignancies (BMT CTN-1101-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.ObjectivesTo compare double unrelated umbilical cord blood and HLA-mismatched (haploidentical) related donor transplantations for the treatment of leukemia and lymphoma in adults.BackgroundEarlier studies have shown that partially HLA-mismatched related bone marrow (haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor cells for Reduced-Intensity Conditioning (RIC) hematopoietic cell transplants (HCT) in patients that do not have access to either an HLA-matched sibling or suitably HLA-matched unrelated donor. Both haplo-BM and dUCB grafts are more accessible for patients lacking an HLA-matched donor.This study assessed the hypothesis that progression-free survival at two years after haplo-BM transplantation is similar to the progression-free survival after dUCB transplantation.ParticipantsPatients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were assigned to undergo double unrelated umbilical cord blood (n = 186) or HLA-mismatched (haploidentical) related donor transplantation (n = 182). Of the 186 patients randomized to the dUCB arm, 172 received the treatment as assigned. Of the 182 patients randomized to the haplo-BM arm, 153 received the treatment as assigned.Enrolled patients had a Karnofsky score greater than or equal to 70% and adequate physical function of the cardiac, hepatic, renal, and pulmonary systems. Furthermore, subjects had one of the following: Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR); Acute Myelogenous Leukemia (AML) in CR1; Acute Leukemias in 2nd or subsequent CR; Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR; adult T-cell leukemia/lymphoma in first or subsequent CR; Burkitt's lymphoma: second or subsequent CR; chemotherapy-sensitive Lymphoma.DesignParticipants were enrolled in the study between June of 2012 and June 2018 and randomized 1:1 using random block sizes stratified by transplant centers (n=33). The primary end point was 2-year progression-free survival (PFS).The donor and recipient in the haplo-BM arm were HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1.Patients enrolled in the dUCB arm had to have two UCB units with a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit was at least 2.0 x10^7/kg. Furthermore, units were HLA matched at a minimum of 4/6 to the recipient at HLA -A, HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high resolution using DNA based typing).All participants received a conditioning regimen/preparative regimen prior to transplant as well as a GVHD prophylaxis regimen.Participants randomized to the dUCB arm received the following conditioning regimen: fludarabine cyclophosphamide, and either 200 or 300 cGy total-body irradiation (TBI). GVHD prophylaxis started 3 days prior to transplantation and included 15 mg/kg mycophenolate mofetil three times daily (with a maximum daily dose of 3 g) through day 35 and cyclosporine adjusted to maintain a trough level of 200 to 400 ng/mL through day 100 and tapered by 10% weekly until discontinued between days 180 and 200.Participants randomized to the haplo-BM received the following conditioning regimen: cyclophosphamide, fludarabine, and 200 cGy TBI. GVHD prophylaxis consisted of 50 mg/kg cyclophosphamide IV daily on days 3 and 4, 15 mg/kg mycophenolate mofetil three times daily from days 5 through 35, and tacrolimus adjusted to maintain a concentration of 5 to 15 ng/mL from day 5 through day 180.ConclusionsThere were no significant differences seen in progression-free survival between double unrelated umbilical cord blood and HLA-mismatched (haploidentical) related donor transplantations for leukemia or lymphoma. Analyses of secondary end points, including overall survival, favored haploidentical BM donors.Fuchs EJ, O'Donnell PV, Eapen M, et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood. 2021;137(3):420-428. doi:10.1182/blood.2020007535

  Study phs004698

• Lung Cancer Genetic Study Among Asian Never Smokers

  The Lung Cancer Genetic Study Among Asian Never Smokers includes data from four population-based studies conducted among Asian women: the Shanghai Women's Health Study (SWHS), the Hwasun Cancer Epidemiology Study (HCES1 and HCES2), the Female Lung Cancer Consortium in Asia (FLCCA, including sFLCA), and the Guangzhou Lung Cancer Study (GLCS). Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Lung cancer patients identified in the SWHS and non-cases were included in the current study.Hwasun Cancer Epidemiology Study-Lung Cancer (HCES1 and HCES2): The HCES is a hospital-based case-control study whose goal is to identify factors of the cancer development and clinical progression in a Korean population. Included in this project were 299 female lung cancer cases from HCES2, who were diagnosed between April 2004 and February 2013 at Chonnam National University Hwasun Hospital, a cancer specified hospital in Jeollanam-do province, South Korea. Controls were randomly selected from women with no previous cancer diagnosis at enrollment in the Namwon Study and the Dong-gu study, ongoing community-based cohort studies in South Korea. A total of 1,103 controls (273 from HCES1 and 830 from HCES2) were genotyped by MEGA. Guangzhou Lung Cancer Study (GLCS): The GLCS is a case-control study including never-smoking women lung cancer cases and controls from Guangzhou, China.In this study, the DNA samples of 1,195 subjects from SWHS and GLCS were genotyped using whole exome sequencing (WES), and the DNA samples of 7,174 subjects from SWHS, HCES1, HCES2, FLCCA, and sFLCA were genotyped using the Multi-Ethnic Global Array (MEGA).

  Study phs002366

• Multi-Omics Study of Lung Cancer in Smokers From EAGLE

  EAGLE (Environment And Genetics in Lung cancer Etiology) is a population-based case-control study examining the full spectrum of lung cancer etiology from smoking initiation, smoking dependency to lung cancer development and outcome. It combines a traditional molecular epidemiology design with more integrative approaches by examining epidemiological, molecular, and clinical data together. To comprehensively investigate the effect of tobacco smoking behaviors on genomic or epigenomic alterations, we performed a multi-omics study including whole-genomic, transcriptomic, and epigenomic profiles in a total of 221 individuals from the EAGLE study.

  Study phs002992

• SCORCH: Revealing the Single Cell Determinants of Brain Relevant to Persistent HIV Infection and Opioid Use Disorder

  People living with HIV (PLWH) are at the higher risk for impaired cognitive functions such as HIV-Associated Neurocognitive Disorder or HAND. Further, higher use of legal and illegal opioids among PLWH could affect their immune functions and exacerbate CNS impairment. However, little is known about the HIV harboring cell types in brain, effect of ART on specific CNS cell types, and the modification of brain functions by opioid use. The human brain is composed of an enormous diversity of cell types defined by distinct gene expression, morphology, connectivity, and physiology. Single cell sequencing assays enable cell type-specific analysis of the role of these cell types in healthy brain function and disease. The overall objective of this proposal is to reveal the single cell determinants of opioid use disorder in the brain relevant to persistent HIV infection using snRNA-seq and snATAC-seq technologies, bioinformatics approaches, and validation studies. Single cell and spatial characterization of HIV and opioid use disorder across multiple regions of the human brain will be performed. These regions may include nucleus accumbens (NAc), prefrontal cortex (PFC), cerebellum, amygdala, and other accessible regions. These results will provide an unprecedented conceptual and experimental system to identify single cell determinants of opioid use disorder in the brain relevant to persistent HIV infection as well as potential opportunities to illuminate how genetic variation affects gene expression.

  Study phs004026