3613 results for "*geneti*"

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• 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