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