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