4002 results for "*geneti*"

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• BLUE CORAL: Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Available Data: Long Term Follow-up data has been added with version 2. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL BLUE CORAL include: Bronchial Lavage, Plasma, Tracheal Aspirate, Urine, Whole Blood Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens is tiered for both non-genetic and genetic research.Objectives: To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19–related hospitalization.Background: For many individuals, the effects of COVID-19 persist after the acute phase and result in prolonged symptoms and disability. This has led to widespread efforts to characterize the epidemiologic characteristics of such post-COVID-19 sequelae. However, accurate data were limited, hindering the ability to counsel patients, caregivers, and policy makers and to plan relevant recovery-focused clinical research. Thus, the BLUE CORAL study was intended to address the knowledge gaps and provide critical data to help guide clinical care, public health, and scientific efforts.Participants: A total of 1376 COVID-19 patents were enrolled, with 825 (444 male, and 379 female) that completed at least one follow-up survey.A subset of the BLUE CORAL adult participants were enrolled in the extension study, FIRE CORAL. FIRE CORAL was a multicenter prospective cohort study of participants recovering from COVID-19 disease after discharge from the hospital. Design: BLUE CORAL was a prospective cohort study. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. Posthospital surveys were administered by trained interviewers in English or Spanish to patients or their proxies at 1, 3, and 6 months after enrollment. Cardiopulmonary symptoms were assessed using the Airways Questionnaire 20, the Kansas City Cardiomyopathy Questionnaire, and the Seattle Angina Questionnaire. Fatigue was assessed using the Patient Health Questionnaire-9. Disability was assessed by self-report of limitations in activities of daily living (ADLs) or instrumental activities of daily living (IADLs). Financial problems were assessed using the World Health Organization Disability Assessment Schedule 2.0 question and questions regarding job changes, time off work, and insurance coverage developed with the Mi-COVID-19 study using qualitative interviews. Quality of life was measured using the European Quality of Life 5-dimension 5-level instrument.The primary outcomes were new or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Symptoms that were not present before hospitalization or specifically reported as increased in severity were counted as new or worsened. Conclusions: The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.

  Study phs003419

• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

  Study phs003793

• Multiple Myeloma Clinical Targeted Sequencing of Patient Samples

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

  Study phs003908

• 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

• NHLBI TOPMed: Genetic Causes of Complex Pediatric Disorders - Asthma (GCPD-A)

  The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is focused on addressing the roles of both single nucleotide variants and structural copy number variants, and their functional impact, together with gene-environment interactions and their influence on asthma drug response.

  Study phs001661

• 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

• Precision High Intensity Training Through Epigenetics (PHITE)

  Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of exercise-induced inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-week exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD). Blood plasma was collected pre- and post exercise at weeks 0 and 12 and after 4 week of detraining upon program completion. Whole-genome enzymatic methylation sequencing (EM-seq) with cell-type proportion deconvolution was applied to cfDNA obtained from the 50 plasma samples and paired to concentration measurements for 90 circulating cytokines. Acute exercise increased the release of cfDNA from neutrophils, dendritic cells (DCs), and macrophages proportional to exercise intensity (HITT > TRAD). Exercise training reduced cfDNA released in HITT participants but not TRAD and from DCs and macrophages but not neutrophils. For most participants, training lowered mitochondrial cfDNA at rest, even after detraining. Using a sequencing analysis approach we developed, we concluded that rapid extracellular traps (ETosis) was the likely source of cfDNA, demonstrated by enrichment of nuclear DNA. Further, several cytokines were induced by acute exercise, such as IL-6, IL-10, and IL-16, and training attenuated the induction of only IL-6 and IL-17F. Cytokine levels were not associated with cfDNA induction, suggesting that these cytokines are not the main cause of exercise-induced cfDNA. Overall, exercise intensity and training modulated cfDNA release and cytokine responses, contributing to the anti-inflammatory effects of regular exercise. One additional subject was also used in the methyl-seq data as a control for comparing bisulfite-sequencing to enzymatic methyl sequencing. DNA methylation for MPO gene was found to be significantly different as well, in line with interpretation that neutrophils are primarily undergoing ETosis.

  Study phs003873

• 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

• Health Effects of Arsenic Longitudinal Study

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

  Study phs003839

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: To determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

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

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

  Study phs003995

• Genomics of Substance Use Disorders in Latin American Populations

  This is a subsample of the National Survey of Drug, Alcohol, and Tobacco Use, administered in 2016 between August and October to participants aged 12-65 in urban and rural Mexican households, named Mexican Genomic Database for Addiction Research (MxGDAR). The objective of the survey was to evaluate the patterns of use of different psychoactive substances and mental health problems in Mexico. The sample universe was made up of primary sampling units (PSUs) that were the sum of basic statistical geographic areas, stratified by state and urban-rural communities. An adult aged 18-65 was chosen randomly from each household, and an adolescent aged 12-17 was also chosen randomly from the household which has at least one member under 18. The second administration of the survey included a subsample of 13,130 respondents who agreed to give a saliva sample for DNA analysis, to be used in analyzing the relationship of mental health, addiction, and genetics. This sample was weighted according to selection probability to be representative on the national level. Mental health symptomatology for these individuals was evaluated using the Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD) using the operational criteria for psychotic disorders (OPCRIT v.4.0), administered by interviewers trained in its use. It includes the evaluation of symptomatology of psychosis, depression, anxiety, obsession/compulsion, mania/hypomania, and post-traumatic stress. The study seeks to replicate genetic associations with substance use (LINC01622), psychiatric disorders (PTPRM), or comorbidity between both (MGMT) reported in following paper: https://pubmed.ncbi.nlm.nih.gov/33762635/. Funding for genotyping was provided by the National Institute on Drug Abuse (NIDA), one of the National Institutes of Health (NIH).

  Study phs003558

• Kids First: Pediatric Research Project on the Genomic Analysis of Congenital Diaphragmatic Hernia

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both, childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. In collaboration with the University of Utah, DNA from four families were selected for high-depth WGS (60X) including diaphragm and skin tissue to identify mosaicism. In collaboration with the Broad Institute, DNA from four families underwent linked long read sequencing using 10X Genomics technology. Probands with congenital diaphragmatic hernia/defects and both biological parents enrolled as part of the DHREAMS study.

  Study phs001110

• SPECIAL (scATACseq): Dissecting the melanoma ecosystem one cell at the time during immunotherapy

  Characterising epigenome profiles of stage III/IV melanoma samples treated with ICB before and on treatment by single cell ATAC sequencing.

  Study EGAS50000001014

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

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

  Study phs003997

• 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

• Field Studies of Human Immunity to Amebiasis in Bangladesh

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

  Study phs001476

• Germline Genomic Analyses of Breast Cancer in Latinas

  In this case-control study of breast cancer among Hispanic/Latina (H/L) women, the goals were to identify breast cancer susceptibility genes and genetic variants for risk of developing breast cancer in H/L women. There were two phases with whole exome sequencing (WES) done in a discovery phase and targeted sequencing of candidate genes in the replication phase. The candidate genes selected for replication came from the first phase and from genes known to affect breast cancer risk in prior studies. Cases and controls were drawn from several studies. Breast cancer cases for discovery phase included women from the City of Hope (COH) Clinical Cancer Genomics Community Research Network (CCGCRN), UCSF Cancer Genetics Clinic and USC Cancer Genetics clinic. Controls for discovery phase included women who did not have breast and were recruited through City of Hope community fairs. A separate group of controls included women from the California Teachers Study. Additional controls for discovery were obtained from WES already generated by the Multi-ethnic cohort (MEC) study. The discovery/WES results of known breast cancer genes were published (PMID 31206626). In the replication phase, we included cases and controls from the Cancer de Mama (CAMA) study which is a case-control study of breast cancer in Mexico, MEC for those not included in the discovery dataset, the San Francisco Bay Area Cancer study (phs000912), the Northern California Breast Cancer Registry, and the California Pacific Medical Center Research Institute Women's Cohort (phs000395). Cases from the PATHWAYS study who were recruited from Northern California Kaiser Permanente were also included. Results from the combined discovery and replication analyses are reported in PMID 36747679.

  Study phs003144

• NHLBI TOPMed: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)

  Subpopulations and Intermediate Outcome Measures in COPD Study Description Subpopulations and intermediate outcome measures in COPD study (SPIROMICS) supports the prospective collection and analysis of phenotypic, biomarker, genetic, genomic, and clinical data from subjects with COPD for the purpose of identifying subpopulations and intermediate outcome measures. It is funded by the National Heart, Lung, and Blood Institute and is coordinated by the University of North Carolina at Chapel Hill. Molecular fingerprinting and extensive subject phenotyping will be performed to identify disease subpopulations and to identify and validate surrogate markers of disease severity, which will be useful as intermediate outcome measures for future clinical trials. Secondary aims are to clarify the natural history of COPD, to develop bioinformatic resources that will enable the utilization and sharing of data in studies of COPD and related diseases, and to create a collection of clinical, biomarker, radiographic, and genetic data that can be used by external investigators for other studies of COPD. Participating Institutions: Research participants for SPIROMICS will be enrolled, phenotyped, and followed at twelve SPIROMICS Clinical Centers: Columbia University, Temple University, Johns Hopkins University, Wake Forest University, University of Michigan, University of Illinois at Chicago, University of Iowa, University of Utah, National Jewish Health, University of California at San Francisco, and University of California at Los Angeles. The University of North Carolina at Chapel Hill serves as the Genomics and Informatics Center. The Radiology Reading Center is based at the University of Iowa. The PFT Reading Center is based at the University of California at Los Angeles. Study Design: SPIROMICS is a prospective cohort study that enrolled approximately 2,981 participants at twelve clinical centers over five years. Participants are distributed across four enrollment strata (i.e., Never-smokers, Smokers without COPD, Mild/Moderate COPD, and Severe COPD). Study Visits: Participants have up to four in-person visits (Baseline and Annual Clinic Visits at years 1, 2, 3 after Baseline). Study questionnaires and spirometry are completed at all main study visits. Blood and urine samples are collected at visits 1, 2, and 4. Sputum samples are collected at Visit 1. The CT scans are completed and Baseline and Visit 2. Participants also receive quarterly follow-up calls to assess health status and determine if an exacerbation has occurred. Substudies Bronchoscopy and Immunophenotyping Substudy The Bronchoscopy Substudy will enroll 50 subjects per site, for a total of 300 participants. These participants will be recruited across all four study strata. This substudy includes two study visits. During the first visit, sputum samples are collected for Immunophenotyping analysis at the Immunophenotyping Core Lab based at the University of Michigan. Participants then return for a second visit during which samples are collected via bronchoscopy, including bronchoalveolar lavage, epithelial brushings and bronchial biopsies. Immunophenotyping analysis is also conducted on BAL and blood collected during the bronchoscopy study visit. Repeatability Substudy The entire baseline clinic visit was repeated on 98 volunteers to determine reliability of measurement procedures. All baseline study-related procedures and questionnaires, including the CT scan, were re-administered and new samples of blood, urine, saliva, and sputum were collected. Field center staff processed these biospecimen samples according to the same protocol. Exacerbation Substudy The Exacerbation Substudy is a prospective, longitudinal observational study of up to 400 participants, which will allow the assessment of participant-driven health care utilization (HCU) events and symptom-defined exacerbation events over time. HCU-driven events are defined by change in medical treatment in response to a perceived COPD Exacerbation. Symptom-based events will be defined by using EXACT-PRO (EXacerbations of Chronic Pulmonary Disease Tool - Patient Reported Outcome), a daily symptom diary developed to measure the frequency, severity, and duration of exacerbations in clinical trials. All participants are provided with a PDA on which to complete the diary. Participants reporting a possible COPD exacerbation will be brought into the study clinic for a study visit to collect biological specimens and questionnaire data. The overall objectives of the Exacerbation Substudy are to: Obtain clinical data and specimens on SPIROMICS participants before and during an acute COPD exacerbation defined by Health care utilization triggered by the subject, or Symptomatic change (triggered by an EXACT defined threshold) Describe symptomatic changes occurring around HCU and symptom-defined (EXACT) events and their relationship to clinical and specimen data, Characterize the non-exacerbation "stable" state in COPD using the EXACT, including: Symptom variability (EXACT), Clinical data and specimen parameters during a stable state (baseline), The relationship between clinical and specimen data and symptom severity and variability. Explore the characteristics of stable patients, defined as those who do not experience HCU or symptom-defined (EXACT) events during the sub-study period, using baseline clinical data and specimens, and compare these characteristics with patients who experience HCU and/or symptom-defined events. Examine the relationship between HCU and symptom-defined exacerbation frequency during the first one-year period of follow-up for exacerbations and health outcomes, including 12-month change in lung function and COPD health status, and longer-term morbidity and mortality, with the latter derived from long-term data from the larger SPIROMICS study.

  Study phs001927

• TRIGR collaboration between University of Helsinkin and Children's Mercy Research Institute

  DAC for collaborations between by the University of Helsinki and Children's Mercy Hospital, such as the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), used to study the evolving epigenomics of immune cells in type 1 diabetes at single nuclei resolution

  Dac EGAC50000000543

• Leukemia Relapse via Genetic Immune Escape after Allogeneic Hematopoietic Cell Transplantation

  Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here we demonstrate, through a broad immunogenetic study, that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and responses to immunomodulatory strategies. These findings define new molecular modes of post-transplant leukemia escape contributing to relapse.The present dataset provides HLA peripheral blood and bone marrow samples supporting the genotyping studies performed for this research. This sample set originates from patients with acute myeloid leukemia or myelodysplastic syndromes receiving allogeneic hematopoietic cell transplantation and relapsing after transplant.

  Study phs003235

• 10x Multiome from Human Fetal Heart

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

  Study phs003778

• Capturing the Genetic Diversity of the Himba Population

  The Himba people are a semi-nomadic, Bantu-speaking pastoralist group from the northwestern Kunene region of Namibia. Because of their limited population size, restricted geographic distribution, and endogamy, founder populations represent an ideal system for genetic analyses due to reduction of the confounding environmental and cultural variables. The original study used genotype data and demographic interview data to understand family dynamics and ancestry in a population of Himba pastoralists. HLA allele calls and genome-wide methylation array data were later generated for a subset of the initial dataset for 2 additional studies. These 3 molecular datasets, available through dbGaP, are relevant to broader studies of ancestry, allele frequencies and the relationship of Himba to other ethnic groups in sub-Saharan Africa. The Himba population provides a unique opportunity to study questions regarding extra-pair paternity and mate selection because Himba culture allows both men and women, married and not, to take multiple partners. Previous estimates of extra-pair paternity rates in human populations have been very low, but these estimates lack global and cultural diversity in population representation. Thus, investigating the rate of extra-pair paternity in the Himba greatly aids in understanding the global variation in non-paternity rates among human populations. Saliva samples were collected from parents and children, and were genotyped on Illumina SNP array platforms (MEGAex and H3Africa). In total, 678 individuals' genotype array data are deposited. Paternity results were de-identified and protected by a double blind protocol (no researcher has full knowledge of individual paternity results). Due to the sensitive nature of this study, paternity assertions are not available for access. For a subset of 360 individuals, HLA class 1 (A, B, C) and class 2 (DPA1, DPB1, DQA1, DQB1, DRB1) genes were targeted for DNA sequencing using a probe-based capture method. HLA alleles at the four field resolution were determined from the sequence capture using the consensus calls obtained from two algorithms: NGSengine® 2.10.0 (GenDX, Utrecht, the Netherlands) and HLA Explore™ (Omixon Biocomputing Ltd. Budapest, Hungary). These data were used to investigate evidence for mate selection based on HLA dissimilarity in the Himba. Himba cultural norms permit concurrent arranged marriages and chosen sexual partnerships allowing us to directly test for evidence of disassortative mate selection based on HLA genotype. Due to the sensitive nature of this study, partnership data are not available for access.For a subset of 51 Himba individuals methylation array data was generated from the saliva-derived DNA. These data were generated in order to investigate the accuracy of epigenetic age predictors in this population and to construct population-specific epigenetic age predictors in a subsequent publication. Chronological ages are available for these 51 individuals.

  Study phs001995

• Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

  The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes". Project 1 addresses the genetics of rare and severe childhood epilepsies, including epileptic encephalopathies (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (periventricular nodular heterotopia and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in multiplex families. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

  Study phs000653

• Genetic Modifiers of Duchenne Muscular Dystrophy

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

  Study phs003680

• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• Kids First: Genetics of Pediatric Germ Cell Tumors

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the genomic and phenotypic data from this study are accessible through dbGaP. The data is also available at the Kids First Portal, where other Kids First datasets can also be accessed in the cloud for data analysis, data visualization, collaboration and interoperability, open to all researchers and developers.Pediatric malignant germ cell tumors (GCTs) represent approximately 6% of childhood cancers, including 3% of tumors in children aged 0-14 years and 15% of tumors in adolescents. GCTs are heterogeneous and grouped together due to the presumed common cell of origin, the primordial germ cell (PGC). GCTs typically occur in the testes or ovaries; however, extragonadal GCTs can occur and are likely a result of abnormal germ cell migration during development. Evidence suggests that GCTs, including those diagnosed in adults, are initiated in utero. Thus, alterations in normal embryonic development are likely to be especially relevant to GCT etiology. Germline susceptibility has not been evaluated in an agnostic fashion in pediatric GCT, mainly due to a lack of an adequate number of samples; however, emerging evidence supports a genetic etiology.In the two Kids First GCT projects, we will evaluate genetic susceptibility to intracranial and extracranial GCT by sequencing probands and their unaffected parents. The goals of the project are to: 1) evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests, focusing on genes and established regulatory regions; 2) identify de novo SNVs and CNVs in pediatric GCT using a case-parent triad design; and 3) identify molecular signatures in GCT tumor specimens, overall and by age group and tumor characteristics. Whole Genome Sequencing (WGS) data generated through the Gabriella Miller Kids First Pediatric Research Program will provide an opportunity to investigate the genetic origins of GCT in a diverse set of samples. Given the limited knowledge of GCT etiology and biology, the results of the proposed analyses are likely to have a big impact on the field.

  Study phs002322

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

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

  Study phs001208

• Genomic Sequencing of Ewing Sarcoma

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

  Study phs000804

• Genetic and Hormonal Contributions to Gene Expression in Immune Cells

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

  Study phs003860

• Childhood Cancer Data Initiative (CCDI): NCI-COG Pediatric MATCH Precision Medicine Clinical Trial

  The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial provides a framework for biomarker-driven early phase trials of targeted therapies in pediatric and young adult cancer patients across the United States. Pediatric MATCH enrolled more than 1,300 patients with treatment-refractory cancers, offering access to molecular screening and investigational targeted therapies. To further advance this, matched diagnostic, refractory tumor, and normal samples from Pediatric MATCH cases were molecularly characterized, creating one of the largest comprehensive data sets available for childhood cancers. This analysis has the potential to provide novel insights into the genetics of refractory pediatric, adolescent, and young adult cancers, as well as inform potential therapeutic strategies. The following molecular characterization assays were performed: Tumor whole exome sequencing (WES) Tumor whole genome sequencing (WGS) Tumor RNA sequencing (RNA-seq) Blood whole exome sequencing (WES) Blood whole genome sequencing (WGS)

  Study phs002883

• dbGaP Collection: NIH Autism -omics Studies

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

  Study phs000764

• Genetic 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

• dbGaP Collection: Open Translational Science in Schizophrenia (OPTICS)

  Schizophrenia is a chronic, severe, disabling brain disorder that affects approximately 1% of the population worldwide. Epidemiologic studies have clearly demonstrated that genetics play a strong role in etiology, but the inheritance is very complex. Innovative analytic approaches and creative ways of combining disparate data sets will be necessary for making breakthroughs in identifying causal pathways and ultimately new drug targets. This dbGaP Collection consists of all genetic studies of schizophrenia available in dbGaP that have been consented for general research use. The goal is to facilitate identification of datasets with related scientific content in order to expedite the application process and ascertainment of datasets of interest for increased scientific discovery. The Open Translational Science in Schizophrenia (OPTICS) Project, was launched by Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with a group of leading research organizations including the National Institutes of Health, Yale University School of Medicine, Rutgers University and the Harvard T.H. Chan School of Public Health, to create a new forum for collaborative analysis of Janssen's schizophrenia clinical trial data and other publicly available data about schizophrenia with the goal of creating new models for conducting research. The OPTICS project is one part of a larger effort at Janssen and other Johnson & Johnson research companies to share clinical trials data to enhance public health and advance science and medicine. Qualified investigators and physicians may apply for access to anonymized clinical trials data from Janssen, for more information please visit https://sites.google.com/site/opticsschizophrenia/.

  Study phs000887

• 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

• CSER: Exome Sequencing in Diverse Populations in Colorado and Oregon/CHARM Cancer Health Assessments Reaching Many

  The CHARM (Cancer Health Assessment Reaching Many) study, part of the Clinical Sequencing Evidence-Generating Research (CS.ER2) effort, aimed to assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population included adults at risk for hereditary cancer syndromes. The primary objective was the implementation of a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators aimed to assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators were also assessing the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.Sequencing and analysis for CHARM was conducted at the Northwest Clinical Genomics Laboratory, University of Washington, Seattle (https://nwgc.gs.washington.edu/).

  Study phs002111

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

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

  Study phs000006

• Genetic and Epigenetic Screens in Primary Human T Cells Link Candidate Causal Autoimmune Variants to T Cell Networks

  We aimed to define the target genes and pathways in which autoimmune disease-associated genetic variants operate. We performed single cell-CRISPR-interference screens in primary human T cells and bulk RNA-seq on T cells containing CRISPRi and single gRNAs to assess how T cell regulatory regions containing autoimmune-associated genetic variants affect nearby gene expression and cellular programs.

  Study phs004072

• DAC for Central African ancient demography processes NGS dataset

  Title DAC Ancient tree-topologies and gene-flow processes among human lineages in Africa Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Short description The Data Access Committee for acess to genotype and sample information used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa" by Gwenna Breton et al. 2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. DNA samples from individuals were collected with the subjects’ informed consent following the Declaration of Helsinki guidelines and approved by the following Ethics committees: Institut de Recherche pour le Développement (IRD, France); Cameroon Ministry of Scientific Research and Technology; Central African Republic Ministère de l’Enseignement Supérieur et de la Recherche Scientifique; France Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation (Comité de Protection des Personnes DC-2016-2740); French Commission Nationale Informatique et Liberté CNIL (declaration n°1972648); Uganda National Council for Science and Technology; Institutional Review Board of the University of Chicago Biological Sciences Division and the Pritzker School of Medicine University of Chicago Hospitals (protocol number 16986A); Committee for the Protection of Human Subjects of the Trustees of Dartmouth College and the Dartmouth-Hitchcock Medical Center (protocol number 22410); Human Research Ethics Committee (Medical) at the University of the Witwatersrand, Johannesburg (Protocol Numbers: M980553, M050902, M090576, M10270, M180654); Working Group of Indigenous Minorities in Southern Africa (WIMSA); South African San Council (SASC); and the Swedish Ethical Review Authority (Dnr 2019-05174). Requests for accessing all or part of the Central African data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), should be addressed to the DAC providing: 1) Data can only be used to explore human genetic evolution, evolutionary ecology and population history 2) The research institution where data will be stored and were analyses will be conducted. 3) The detailed coordinates of the researcher responsible for data storage and analyses. 4) A description (max 20 sentences) of the scientific finality and context of the project and classes of methodological analyses that will be performed to achieve it using the requested data. 5) When applicable, mention also other previously published data sets that will be used jointly with the requested datas et For accessing any or all the Central African genetic data used in the article "Ancient tree-topologies and gene-flow processes among human lineages in Africa", by Gwenna Breton et al. 2024 (doi - PENDING), the requester hereby ensures that: 1) Individual donor privacy should be respected at all times. Data cannot be made publicly available under any circumstances. 2) Data cannot be shared nor transferred to a third party without re-applying for eGA access to the DAC. 3) No direct or indirect commercial use of the data can be made 4) No individual medical genetics or disease diagnostics can be performed with the data 5) No medical or legal forensic investigations can be conducted with the data 6) No genealogical research can be conducted with the data (e.g. no paternity nor maternity testing, no genetic identification, no search of relatives using other datasets) 7) Appropriate citation of the article and data set used for any scientific communication using the data 8) Data is destroyed after the completion of the project. Any further re-use of the data is subject to a novel application to the DAC.

  Dac EGAC50000000447

• Uncovering Gene Regulatory Differences between Human and Chimpanzee Neural Cells

  A major challenge in human evolutionary biology is to pinpoint the genetic differences that underlie phenotypic changes in the human lineage, such as increased neuron number and a prolonged period of neuronal maturation. Here, we used human-chimpanzee tetraploid cells to distinguish changes in gene expression due to cis-acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment, in neural progenitor cells and excitatory neurons using RNA-seq and ATAC-seq. Using a CRISPR inhibition screen with scRNA-seq, transcription factor motif analyses with CUT&Tag, and downstream single-locus studies with RNA-seq, we further characterized cis-acting gene regulatory differences, including changes to FOS, TNIK, FOSL2, and MAZ, that influence neurogenesis and neuronal maturation. This study identifies specific genomic changes that may contribute to human neural specializations and provides a general framework for understanding genetic differences that underlie human traits.

  Study phs004053

• Genome Sequencing and Variant Calling of HCM Patients with MYH7 Variants

  To investigate potential genetic causes of cardiomyopathy we recruited 48 patients harboring rare MYH7 variants identified from panel-based testing and with a clinical manifestation of cardiomyopathy. Genome sequencing was performed to identify other potential causative variants and genetic modifiers of the cardiomyopathy phenotype, which varied among patients.

  Study phs004024

• Identifying the Genetic Basis of Variably Protease-Sensitive Prionopathy (VPSPr)

  Design: Sequencing of cases onlyMolecular technologies: Exome sequencing and custom targeted sequencing of PRNPAims: Identify modestly penetrant, high odds ratio variants conferring risk of variably protease-sensitive prionopathy (VPSPr)Population: n=67 autopsy-confirmed VPSPr cases, United States, 1997-2021Principal findings: Association to PRNP M129V replicated, no other causal variants identifiedData available: Raw sequencing data and metadata

  Study phs004012

• Epigenetic Control of Topoisomerase 1 by MacroH2A1.1

  DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic single-stranded DNA lesions (SSLs). What protects the genome from aberrant TOP1 activity remains unknown. Using a combination of CUT&RUN and TOP1 Covalent Adduct Detection (CAD) Seq in MDA-MB-231 breast cancer cells (American Type Culture Collection, ATCC), we identified chromatin context as an essential means to ensure TOP1cc resolution at TOP1 hot spots. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. MacroH2A1 isoform-specific analyses were based on reconstitution of macroH2A1.1 knockout cells with wild-type or PAR binding-deficient FLAG-tagged macroH2A1.1 in human breast cancer cells. Mechanistically, we find that macroH2A1.1 facilitates the recruitment of the TOP1cc repair factor XRCC1 in response to both endogenous and drug-induced topological stress. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect in breast and ovarian cancer cells. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors (TOP1i). We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

  Study phs003729

• Omic Studies in Children's Respiratory and Environmental Workgroup (CREW) Cohorts

  Children's Respiratory Research Workgroup (CREW) is an NIH-funded project consisting of multiple individual U.S. cohorts and three scientific centers working together to identify phenotypes and causes of childhood asthma. CREW will include data from a large number of children and their families, with broad diversity in terms of ethnicity, family characteristics, neighborhoods and geographic locations. One of the primary goals of CREW is to put together sets of data and samples of participating cohorts to identify phenotypes of childhood asthma (i.e. specific subtypes of asthma that can be distinguished by clinical features such as natural history, triggers, exacerbation frequency, concurrent allergies, lung function, sex, etc). Omics studies will include genotyping, methylation, and RNA sequencing. By integrating the DNA genotyping with the expression, immunologic and clinical data, we will identify eQTL, inflammation QTL, and lung function QTL, as well as QTL associated with other biomarkers. Analyses will identify genetic, epigenetic, transcriptional and protein/metabolite profiles that are associated with specific exposures or phenotypes. As we obtain mechanistic insights about personal and early life risk factors, we will connect asthma phenotypes with underlying causes and pathogenic mechanisms to define endotypes of childhood asthma.

  Study phs004036

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

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

  Study phs004080

• Re-Evaluation of Systemic Early Neuromuscular Blockade

  This study of the ROSE trial data explored two distinct molecular subtypes of ARDS (Acute Respiratory Distress Syndrome) to better understand the disease's complexity and potential for personalized treatment. Previous studies had identified different inflammatory profiles in ARDS patients, with this research addressing three key questions: Can these molecular subtypes be consistently identified in a more severe group of ARDS patients? Do these subtypes respond differently to neuromuscular blockade treatment? What specific biological processes differentiate these inflammatory profiles? Advanced transcriptomic and protein analyses examined blood samples from ARDS patients. Analysis of these data revealed two main molecular phenotypes: Hypoinflammatory phenotype (60.4% of patients) Hyperinflammatory phenotype (39.6% of patients) Key findings demonstrated that the hyperinflammatory subtype was associated with:Significantly higher mortality rates relative to hypoinflammatory (61.6% vs. 30.3%)Significantly higher mortality rates relative to hypoinflammatory (61.6% vs. 30.3%)Distinct gene expression patterns related to immune responseUnique changes in genes associated with tissue remodeling and cellular processes Notably, the neuromuscular blockade treatment showed no difference in effects across these subtypes. Complex relationships emerged between gene expression and protein levels, with some genes closely matching their protein counterparts and others displaying more variable connections. The study concludes that these molecular phenotypes possess distinct clinical, protein, and genetic characteristics, suggesting potential for more precise, personalized approaches to ARDS treatment in the future.

  Study phs003929

• Oncogenome of Kaposi Sarcoma

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

  Study phs003897

• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

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

  Study phs003641

• NHLBI TOPMed: Lung Tissue Research Consortium (LTRC)

  Chronic obstructive pulmonary disease (COPD), a disease state characterized by airflow limitation that is not fully reversible, is the third leading cause of death in the U.S. COPD is a heterogeneous syndrome, with affected individuals demonstrating marked differences in lung structure (emphysema vs. airway disease); physiology (airflow obstruction); and other clinical features (e.g., exacerbations, co-morbid illnesses). Multiple genomic regions influencing COPD susceptibility have been identified by genome-wide association studies (GWAS), and rare coding variants can also influence risk for COPD. However, only a small percentage of the estimated heritability for COPD risk can be explained by known genetic loci. Like most complex diseases, COPD is influenced by multiple genetic determinants (each with modest individual effects). Emerging evidence supports the paradigm that complex disease genetic determinants are part of a network of interacting genes and proteins; perturbations of this network can increase disease risk. To identify this network, multiple Omics data will need to be analyzed with methods to account for nonlinear relationships and interactions between key genes and proteins. Our overall hypothesis is that integrated network analysis of genetic, transcriptomic, proteomic, and epigenetic data from biospecimens ranging from lung tissue to nasal epithelial cells to blood in highly phenotyped subjects will provide insights into COPD pathogenesis and heterogeneity. We will leverage the well-phenotyped, NHLBI-funded Lung Tissue Research Consortium (LTRC) to address these questions. We will perform multi-omics analysis in 1548 lung tissue and blood samples from the LTRC. With these multi-omics data, we will utilize a systems biology approach to understand relationships between multiple genetic determinants and multiple types of Omics data. We will begin by performing single Omics analyses in COPD vs. control lung, nasal, and blood samples. Next, we will integrate single Omics data with genetic variants identified by WGS to assist in fine mapping genetic determinants of COPD. We will then perform integrated network analysis of COPD with genetic and multiple Omics data using correlation-based, gene regulatory, and Bayesian networks. Subjects were recruited from Mayo Clinic, Universities of Colorado, Michigan, and Pittsburgh, and Temple University.

  Study phs001662

• HBCC Postmortem Psychiatric Molecular Studies

  This postmortem study examines molecular, genetic and epigenetic signatures in the brains of hundreds of subjects with or without mental disorders conducted by the DIRP NIMH Human Brain Collection Core (HBCC). The brain tissues are obtained under protocols approved by the CNS IRB (NCT00001260), with the permission of the next-of-kin (NOK) through the Offices of the Chief Medical Examiners (MEOs) in the District of Columbia, Northern Virginia and Central Virginia. Additional samples were obtained from the University of Maryland Brain and Tissue Bank (contracts NO1-HD-4-3368 and NO1-HD-4-3383) (http://www.medschool.umaryland.edu/btbank/ and the Stanley Medical Research Institute: http://www.stanleyresearch.org/brain-research/). Clinical characterization, neuropathological screening, toxicological analyses, and dissections of various brain regions were performed as previously described (Lipska et al. 2006; PMID: 16997002). All patients met DSM-IV criteria for a lifetime Axis I diagnosis of psychiatric disorders including schizophrenia or schizoaffective disorder, bipolar disorder and major depression. Controls had no history of psychiatric diagnoses or addictions. SNP array: Array-based genotyping was performed on most samples published in this collection. The number of SNPs assayed via Illumina chips varied between 650,000 and 5 Million. Cerebellar tissue was generally used for genotyping studies. # Diagnosis SNP Array 1 Anxiety Disorder 1 2 Autism Spectrum Disorder 13 3 Bipolar Disorder 114 4 Control 387 5 Eating Disorder (ED) 2 6 Major Depressive Disorder (MDD) 186 7 Obsessive Compulsive Disorder (OCD) 5 8 Post-Traumatic Stress Disorder (PTSD) 0 9 Schizophrenia 220 10 Other 7 11 Tic Disorder 3 12 Undetermined 1 13 Williams Syndrome 2 Table: Numbers of samples in each diagnostic category. DNA extraction: 45-80 mg of cerebellar tissue was pulverized for DNA extractions. The QIAamp DNA mini Kit (Qiagen) method was employed for tissue DNA extraction. The tissue was initially lysed using Tissue Lyser (Qiagen) and extractions were accomplished according to manufacturer's protocol. The DNA was captured in 500uL elution buffer. The concentrations were measured using Thermo Scientific's NanoDrop 1000/NanoDrop ONE. The mean yield was 128.85 uG (+/- 79.48), the mean ratio of 260/280 was 1.87 (+/- 0.105), and the mean ratio of 260/230 was 2.48 (+/-1.75). Genotyping methods: Three types of Illumina Beadarray chips were used: HumanHap650Y, Human1M-Duo, and HumanOmni5M-Quad (San Diego, California). The genotyping was done according to the manufacturer's protocol (Illumina Proprietary, Catalog # WG-901-5003, Part # 15025910 Rev.A, June 2011). Approximately, 400ng DNA was used and each DNA sample was QC tested for 260/280 ratio by nanodrop and DNA band intactness on 2% agarose gel. Briefly, the samples were whole-genome amplified, fragmented, precipitated and resuspended in appropriate hybridization buffer. Denatured samples were hybridized on prepared Bead Array Chips. After hybridization, the Bead Chip oligonucleotides were extended by a single fluorescent labeled base, which was detected by fluorescence imaging with an Illumina Bead Array Reader, iScan. Normalized bead intensity data obtained for each sample were loaded into the Illumina Genome Studio (Illumina, v.2.0.3) with cluster position files provided by Illumina, and fluorescence intensities were converted into SNP genotypes. Microarray: We generated RNA expression data using array technology for psychiatric subjects compared to non-psychiatric subjects as controls. We used tissues from three different brain regions i.e. hippocampus, dorsolateral prefrontal cortex (DLPFC), and dura mater for a large cohort of individuals (total number 552 subjects for hippocampus, 800 for DLPFC and 146 for dura). Total RNA was extracted from ~100 mg of tissue using the RNeasy kit (Qiagen) according to the manufacturer's protocol. RNA quality and quantity were examined using the Bioanalyzer (Agilent, Inc) and NanoDrop (Thermo Scientific, Inc), respectively. Samples with RNA integrity number (RIN) # Diagnosis DLPFC Hippo Dura 1 Anxiety Disorder 1 0 0 2 Autism Spectrum Disorder 14 6 0 3 Bipolar Disorder 90 49 0 4 Control 336 270 75 5 Eating Disorder (ED) 2 1 0 6 Major Depressive Disorder (MDD) 144 87 0 7 Obsessive Compulsive Disorder (OCD) 5 3 0 8 Post-Traumatic Stress Disorder (PTSD) 6 0 0 9 Schizophrenia 192 125 71 10 Other 5 6 0 11 Tic Disorder 3 3 0 12 Undetermined 1 1 0 13 Williams Syndrome 2 1 0 Table: Numbers of samples in each diagnostic category. RNA-Seq of Dorso-lateral prefrontal cortex: All brains were collected and the dorsolateral prefrontal cortical (DLPFC) samples dissected at the HBCC, DIRP, NIMH. Dorsolateral prefrontal cortex (DLPFC) specimens were dissected from right or left hemisphere of frozen coronal slabs. The study was funded by the DIRP, NIMH under contract (#HHSN 271201400099C) with Icahn School of Medicine at Mount Sinai,1106402 One Gustave L. Levy Place, Box 3500, New York NY 10029-6574. RNA extraction, library preparation and sequencing were performed under contract at Icahn School of Medicine. The Common Mind Consortium (CMC) provided project management support. RNA isolation: Total RNA from 468 HBCC samples was isolated from approximately 100 mg homogenized tissue from each sample by TRIzol/chloroform extraction and purification with the Qiagen RNeasy kit (Cat#74106) according to manufacturer's protocol. Samples were processed in randomized batches of 12. The order of extraction for schizophrenia, bipolar, and MDD disorders and control samples was assigned randomly with respect to diagnosis and all other sample characteristics. The mean total RNA yield was 24.2 ug (+/- 9.0). The RNA Integrity Number (RIN) was determined by 4200 Agilent TapeStation System. Samples with RIN DLPFC RNA-Seq quantified expression data are provided for 364 samples. Data were generated, QC'd, processed and quantified as follows: RNA library preparation and sequencing: All samples submitted to the New York Genome Center for RNAseq were prepared for sequencing in randomized batches of 94. The sequencing libraries were prepared using the KAPA Stranded RNAseq Kit with RiboErase (KAPA Biosystems). rRNA was depleted from 1ug of RNA using the KAPA RiboErase protocol that is integrated into the KAPA Stranded RNAseq Kit. The insert size and DNA concentration of the sequencing library was determined on Fragment Analyzer Automated CE System (Advanced Analytical) and Quant-iT PicoGreen (ThermoFisher) respectively. Schizophrenia Bipolar Control 89 65 210 Table: Numbers of samples in each diagnostic category. RNA-Seq of subgenual anterior cingulate cortex (sgACC): All the 200 post-mortem brain samples (61 controls; 39 bipolar disorder; 46 schizophrenia; 54 major depressive disorder) were collected by the HBCC, DIRP, NIMH. RNA Extraction and Quality Assessment: Tissue from sgACC was pulverized and stored at -80°C. Total RNA was extracted from 50-80 mg of the tissue using QIAGEN RNeasy Lipid Tissue Mini Kit (QIAGEN, Cat. # 74804) with DNase treatment (QIAGEN, Cat. # 79254). The RNA Integrity Number (RIN) for each sample was assessed with high-resolution capillary electrophoresis on the Agilent Bioanalyzer 2100 (Agilent Technologies, Palo Alto, California). The concentration of RNA and their 260/280 ratio (2.1+/- 0.032 SD) were determined with NanoDrop (Thermo Scientific). RNA sequencing: Stranded RNA-Seq libraries were constructed after rRNA depletion using Ribo-Zero GOLD (Illumina). RNA sequencing was performed at National Institute of Health Intramural Sequencing Center (NISC). Schizophrenia Bipolar Control MDD 46 39 61 54 Table: Numbers of samples in each diagnostic category. Whole Genome Sequencing: All brains were collected and dissected at the HBCC, DIRP, NIMH. This study generates whole genome sequencing data using sequencing of DNA in the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) or cerebellum of 443 individuals with schizophrenia, bipolar disorder and major depressive disorder and non-psychiatric controls. The study was funded by the DIRP, NIMH under contract (#HHSN 271201400099C) with Icahn School of Medicine at Mount Sinai,1106402 One Gustave L. Levy Place, Box 3500, New York NY 10029-6574. DNA extraction, library preparation and sequencing were performed under contract at Icahn School of Medicine. The Common Mind Consortium (CMC) provided project management support. All specimens were dissected from right or left hemisphere of frozen coronal slabs. DNA Library Preparation and Sequencing: All samples submitted to the New York Genome Center for WGS were prepared for sequencing in randomized batches of 95. The sequencing libraries were prepared using the Illumina PCR-free DNA sample preparation Kit. The insert size and DNA concentration of the sequencing library was determined on Fragment Analyzer Automated CE System (Advanced Analytical) and Quant-iT PicoGreen (ThermoFisher) respectively. A quantitative PCR assay (KAPA), with primers specific to the adapter sequence, was used to determine the yield and efficiency of the adaptor ligation process. Performed on the Illumina HiSeqX with 30X coverage. Schizophrenia Bipolar Control 115 78 230 Table: Numbers of samples in each diagnostic category. ChIP-Seq: All brains were collected and the dorsolateral prefrontal cortical (DLPFC) samples dissected at the HBCC, DIRP, NIMH. This study generates epigenetic data using sequencing of DNA after chromatin immunoprecipitation (ChIP-Seq) for marks H3K4me3 and H3K27ac in the dorsolateral prefrontal cortex (DLPFC). Dorsolateral prefrontal cortex (DLPFC) specimens were dissected from right or left hemisphere of frozen coronal slabs. The study was funded by the DIRP, NIMH under contract (#HHSN 271201400099C) with Icahn School of Medicine at Mount Sinai,1106402 One Gustave L. Levy Place, Box 3500, New York NY 10029,6574. Chromatin precipitation, library preparation and sequencing were performed under contract at Icahn School of Medicine. The Common Mind Consortium (CMC) provided project management support. Chromatin immunoprecipitation (ChIP) assays for histone marks H3K4me3 and H3K27ac were carried out using Native ChIP. Micrococcal Nuclease (MNase) (Sigma, N3755) treatment was used to digest chromatin into mononucleosomes. The following antibodies were used for chromatin pull-down: anti-H3K4me3 (Cell Signaling, Cat# 9751BC, lot 7) and anti-H3K27ac (Active Motif, Cat# 39133, Lot # 31814008). Histone modification-enriched genomic DNA fragments were recovered using Protein A/G magnetic beads (Thermo Scientific, 88803-88938 or Millipore 16-663), and then washed, eluted, and treated with RNAse A and proteinase K. Final ChIP DNA products were isolated using phenol-chloroform extraction followed by ethanol precipitation. The efficiency of each ChIP assay was validated using Qubit concentration measurement and qPCR for positive (GRIN2B, DARPP32) and negative (HBB) control genomic regions. Only ChIP assays that passed quality control were further processed for library preparation and sequencing; this included ChIP DNA that was not detectable on Qubit but showed a good signal and expected enrichment patterns in qPCR. HISTONE_MARK H3K27ac H3K4me3 Input Bipolar 56 4 7 Control 158 11 24 Schizophrenia 79 11 12 Table: Numbers of individuals in each assay grouped by histone mark or input.Long-Read Whole-Genome Sequencing (WGS) Cohort Description: Brain specimens were obtained from the Human Brain Collection Core (HBCC), part of the NIH NeuroBioBank. Samples were collected under protocols approved by the NIH CNS Institutional Review Board (IRB) (NCT03092687), with informed consent from next-of-kin (NOK). Collection was coordinated through the Offices of the Chief Medical Examiners (MEOs) in Washington, D.C., Northern Virginia, and Central Virginia. Clinical metadata and documentation are publicly available via the NIMH Data Archive (NDA) (Collection #3151) https://nda.nih.gov/edit_collection.html?id=3151 Eligibility Criteria No clinical diagnosis of major neuropsychiatric or neurodegenerative diseaseNo diagnosis of cognitive impairment during life All individuals were confirmed to be neurologically normal at time of deathDemographics Initial cohort size: 155 individuals Ancestry: All individuals self-identified as African or African-admixed Mean age at death: 44.2 years (range: 18–85 years) Sex distribution: 36.4% femaleSample Processing: Frozen frontal cortex tissue was dissected and processed according to the public protocol: https://www.protocols.io/view/processing-human-frontal-cortex-brain-tissue-for-p-kxygxzmmov8j/v2. High-molecular-weight DNA was extracted and libraries were prepared using the Oxford Nanopore Technologies (ONT) LSK-114 kit. Sequencing was performed using ONT PromethION flow cells (R10.4.1 chemistry) Data Processing and Quality Control: Basecalling: Conducted using Guppy v6.38 Read Alignment: Reads were aligned to the GRCh38 reference genome using minimap2 Sample Identity Verification: Sample identity was validated by comparing ONT-derived SNP calls with matched short-read WGS genotypes to ensure concordance and prevent sample swaps Variant Calling and Phasing: Reads were base-called with Guppy v6.38. Reads were aligned to GRCh38 using minimap2. We verified sample identity by cross-checking ONT SNV calls with the existing short-read WGS genotypes, confirming no sample switches. The napu pipeline (https://github.com/nanoporegenomics/napu_wf) produced; haplotype-resolved assemblies, joint small-variant (SNV/indel) calls, and multi-caller structural-variant sets, all reported on GRCh38 and phased where possible. Raw signal data were basecalled to obtain 5-methyl-cytosine (5mC) status; methylation tags were added to the phased BAM files. Genome-wide methylation summaries are provided in BED format.Dataset Filtering and Exclusions: All 155 samples underwent sequencing and SNP-based ancestry inference 8 samples were excluded due to ancestry inconsistent with African or African-admixed background 1 sample was excluded due to insufficient sequencing quality Final Sample Set: 146 high-quality samples from individuals of African or African-admixed ancestry were retained for downstream analyses See PMID: 39764002 for further analysis detailsDiagnosis#SamplesControl155Table: Diagnostic Summary.Note: The data derived from HBCC resources were removed from dbGAP and are now available in the NIMH Data Archive (NDA). They include genotypes, short read whole genome sequencing (WGS), epigenetics (DNA methylation, ChIP-seq for histones), RNA expression (qPCR, microarray, RNA-seq, single nucleus RNA-seq) of various brain regions in cases with schizophrenia, bipolar disorder, major depression, substance use disorders and normative controls. Please access our NDA collection (https://nda.nih.gov/edit_collection.html?id=3151) for further detail.

  Study phs000979

• Biallelic loss of function PAX4 variants are a Novel Cause of Transient Neonatal Diabetes

  The identification of genes in which loss of function (LoF) variants cause neonatal diabetes mellitus (NDM) can provide unique insights into the development and function of human pancreatic beta cells. We describe the identification of biallelic PAX4 LoF variants in 2 unrelated individuals with transient NDM: one due to a homozygous p.(Arg126*) PAX4 stop gain variant and a second due to a homozygous c.-352_104del 2.65kb deletion affecting the first 4 exons and promoter of the PAX4 Matched Annotation from NCBI and EMBL-EBI select transcript. We confirmed reduced transcript expression due to nonsense mediated decay for the e p.(Arg126*) variant in CRISPR-edited iPSC-derived pancreatic endoderm cells. Analysis of PAX4 binding through integration of CUT&RUN and RNA-sequencing in PAX4 depleted endocrine cells identified genes directly regulated by PAX4 involved in both pancreatic islet development and glucose-sensitive insulin secretion. The remitting and relapsing diabetes in both probands demonstrates that in contrast to mice PAX4 is not essential for the development of pancreatic beta-cells and supports differences in the requirements of functional beta-cell mass across the life-course.

  Study EGAS50000000857

• DAC for EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer

  This is the Data Access Committee for the EGA study: Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer (temp ID 800).

  Dac EGAC50000000563

• Identifying genetic variants that alter TCR usage in the peripheral repertoire

  The relationship between genetic variation and CD8+ T-cell receptor (TCR) repertoire usage in patients receiving Immune Checkpoint Blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ T-cell TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-mer usage from samples taken prior to and after ICB (n=250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, whilst at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with novel implications for understanding factors relating to therapeutic response and patient outcomes.

  Study EGAS00001008189

• Human Epilepsy Genetics: Mosaic Mutations in Focal Epilepsy

  This study investigates the role of somatic mosaic mutations in human focal epilepsies, including focal cortical dysplasia (FCD) and mesial temporal lobe epilepsy (mTLE). It leverages genomic and single-cell transcriptomic data from surgically resected brain tissue to identify pathogenic variants and characterize their effects on specific cell types and molecular pathways. The study employs methods such as deep whole-exome and targeted sequencing, single-nucleus RNA sequencing (snRNA-seq), and integrated genotype-transcriptome profiling (e.g., GO-TEN) to define the cellular architecture and functional consequences of mosaic mutations. Data generated under this project aim to elucidate mechanisms of epileptogenesis and support discovery of potential therapeutic targets.

  Study phs004124

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

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

  Study phs001974

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

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

  Study phs004180

• Single Cell DNA Methylation Analysis for Forensic Epigenetics

  As part of the Epigenetic CHaracterization and Observation (ECHO) program, the Genomic Analysis Laboratory at the Salk Institute generated the DNA methylation profiles of certain PBMC cell types to determine the change in methylation levels before, during or after exposure to certain biological or chemical agents. Samples from individuals who either handled anthrax in controlled environments or who tested positive to MRSA, MSSA, HIV, COVID-19 or exposed to Flu virus or organophosphates, or control samples were used in single-nucleus methylation (snmC-seq) assays to quantify DNA methylation levels of cytosine residues of the DNA. Around 5-10% cytosine sites were sampled in the assay. Using computational analyses, regions in the genome differentially methylated in response to the exposure were identified. This information can be used to develop diagnostic tools to predict the type of infection or time since exposure.

  Study phs003204

• 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

• Genetics and Pathobiology of Disorders of Keratinization

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

  Study phs004172

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

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

  Study phs004075

• Framingham Cohort

  Startup of Framingham Heart Study. Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. In 1948, the Framingham Heart Study (FHS) -- under the direction of the National Heart Institute (now known as the National Heart, Lung, and Blood Institute, NHLBI) -- embarked on a novel and ambitious project in health research. At the time, little was known about the general causes of heart disease and stroke, but the death rates for CVD had been increasing steadily since the beginning of the century and had become an American epidemic. The objective of the FHS was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Design of Framingham Heart Study. In 1948, the researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have returned to the study every two years for an examination consisting of a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a second-generation cohort -- 5,124 of the original participants' adult children and their spouses -- to participate in similar examinations. The second examination of the Offspring cohort occurred eight years after the first examination, and subsequent examinations have occurred approximately every four years thereafter. In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort. The first examination of the Third Generation Study was completed in July 2005 and involved 4,095 participants. Thus, the FHS has evolved into a prospective, community-based, three generation family study. The FHS is a joint project of the National Heart, Lung and Blood Institute and Boston University. Research Areas in the Framingham Heart Study. Over the years, careful monitoring of the FHS population has led to the identification of the major CVD risk factors -- high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity -- as well as a great deal of valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Risk factors have been identified for the major components of CVD, including coronary heart disease, stroke, intermittent claudication, and heart failure. It is also clear from research in the FHS and other studies that substantial subclinical vascular disease occurs in the blood vessels, heart and brain that precedes clinical CVD. With recent advances in technology, the FHS has enhanced its research capabilities and capitalized on its inherent resources by the conduct of high resolution imaging to detect and quantify subclinical vascular disease in the major blood vessels, heart and brain. These studies have included ultrasound studies of the heart (echocardiography) and carotid arteries, computed tomography studies of the heart and aorta, and magnetic resonance imaging studies of the brain, heart, and aorta. Although the Framingham cohort is primarily white, the importance of the major CVD risk factors identified in this group have been shown in other studies to apply almost universally among racial and ethnic groups, even though the patterns of distribution may vary from group to group. In the past half century, the Study has produced approximately 1,200 articles in leading medical journals. The concept of CVD risk factors has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice. In addition to research studies focused on risk factors, subclinical CVD and clinically apparent CVD, Framingham investigators have also collaborated with leading researchers from around the country and throughout the world on projects involving some of the major chronic illnesses in men and women, including dementia, osteoporosis and arthritis, nutritional deficiencies, eye diseases, hearing disorders, and chronic obstructive lung diseases. Genetic Research in the Framingham Heart Study. While pursuing the Study's established research goals, the NHLBI and the Framingham investigators has expanded its research mission into the study of genetic factors underlying CVD and other disorders. Over the past two decades, DNA has been collected from blood samples and from immortalized cell lines obtained from Original Cohort participants, members of the Offspring Cohort and the Third Generation Cohort. Several large-scale genotyping projects have been conducted in the past decade. Genome-wide linkage analysis has been conducted using genotypes of approximately 400 microsatellite markers that have been completed in over 9,300 subjects in all three generations. Analyses using microsatellite markers completed in the original cohort and offspring cohorts have resulted in over 100 publications, including many publications from the Genetics Analysis Workshop 13. Several other recent collaborative projects have completed thousands of SNP genotypes for candidate gene regions in subsets of FHS subjects with available DNA. These projects include the Cardiogenomics Program of the NHLBI's Programs for Genomics Applications, the genotyping of ~3000 SNPs in inflammation genes, and the completion of a genome-wide scan of 100,000 SNPs using the Affymetrix 100K Genechip. Framingham Cohort Phenotype Data. The phenotype database contains a vast array of phenotype information available in all three generations. These will include the quantitative measures of the major risk factors such as systolic blood pressure, total and HDL cholesterol, fasting glucose, and cigarette use, as well as anthropomorphic measures such as body mass index, biomarkers such as fibrinogen and CRP, and electrocardiography measures such as the QT interval. Many of these measures have been collected repeatedly in the original and offspring cohorts. Also included in the SHARe database will be an array of recently collected biomarkers, subclinical disease imaging measures, clinical CVD outcomes as well as an array of ancillary studies. The phenotype data is located here in the top-level study phs000007 Framingham Cohort. To view the phenotype variables collected from the Framingham Cohort, please click on the "Variables" tab above. The Framingham Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000007 Framingham Cohort. phs000342 Framingham SHARe phs000282 Framingham CARe phs000363 Framingham SABRe phs000307 Framingham Medical Resequencing phs000401 Framingham ESP Heart-GO phs000651 Framingham CHARGE-S phs000724 Framingham DNA Methylation phs001610 Framingham T2D-GENES phs002558 Framingham ADSP phs002559 Framingham BRIDGET phs002560 Framingham Cholesterol phs002611 Framingham Post-Mortem Brain Tissue phs002938 Framingham Molecular QTL The unflagging commitment of the research participants in the NHLBI FHS has made more than a half century of research success possible. For decades, the FHS has made its data and DNA widely available to qualified investigators throughout the world through the Limited Access Datasets and the FHS DNA Committee, and the SHARe database will continue that tradition by allowing access to qualified investigators who agree to the requirements of data access. With the SHARe database, we continue with an ambitious research agenda and look forward to new discoveries in the decades to come.

  Study phs000007

• WES data of pediatric cancer patients with P/LP variants in HBOC-related genes

  The current study aimed to identify (likely) pathogenic germline variants(LP/PVs) in 25 adult-onset HBOC-related genes within a cohort of 372 pediatric cancer patients. For this purpose we performed (paired-end) whole exome sequencing (WES) using Ilumina sequencing technology. The files uploaded here belong to the 27 individuals with such a LP/PV. The project provides insight into the prevalence and spectrum of such variants in childhood cancer, contributing to the understanding of genetic predisposition in pediatric oncology.

  Dataset EGAD50000001561

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000658

• Whole-exome-sequencing in Motor neuron disease (MND)

  To identify the genetic cause and modifiers of Motor neuron disease (MND), we performed Whole-exome-sequencing of Motor neuron disease (MND) patients.

  Study JGAS000422

• Transcriptome of human trophoblast stem cells derived from normal and HDP placentas

  Hypertensive disorders of pregnancy (HDP) is a disease driven by abnormal placenta formation, which is a leading cause of maternal and fetal death. For investigation of genetic and epigenetic regulation of human trophoblast differentiation, we have previously established human trophoblast stem cells (hTSCs) from first-trimester placentas. Those hTSCs were able to differentiate into extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STs), and their transcriptome was similar to that of cytotrophoblasts in human placenta. However, since HDP happens in the second half of pregnancy, the conventional hTSC derivation method was not enough to investigate the nature of HDP trophoblasts. In this analysis, we improved the derivation method and successfully established the hTSCs from normal and HDP term placentas after delivery. We performed RNA-seq of normal and HDP hTSCs, and HDP hTSCs recapitulated abnormalities in gene expression reported in HDP placentas.

  Study JGAS000660

• Biomarker Research for Anti EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics

  The purpose of this study is to explore new biomarkers for predicting the effectiveness of an anti-epidermal growth factor receptor (anti-EGFR) antibody in patients with advanced colorectal cancer. The investigation involves analyzing the entire exome, conducting a genome-wide association study (GWAS), and analyzing copy number variations (CNVs) using single nucleotide polymorphism (SNP) arrays. Genetic material from both cancerous and non-cancerous tissues, as well as blood samples from patients who received the antibody treatment, will be used. The goal is to identify genetic mutations and SNPs associated with treatment efficacy and adverse events, and to assess the correlation between their presence and treatment effectiveness using statistical methods.

  Study JGAS000779

• Elucidating the development of cervical cancer and identifying therapeutic targets based on cancer genome analysis.

  The objective of this project is to analyze genomic aberrations and gene expression changes, such as mutations, deletions, and amplifications, in human cervical cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lcervical cancer development and progression at the genetic level.

  Study JGAS000803

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established three kinds of esophageal tumoroids derived from esophageal cancer patient. We performed whole exome sequencing to analyze genetic background of the tumoroids.

  Study JGAS000749

• Reference Panel for Imputation Analysis Based on Whole Genome Sequencing Data of 3,256 Japanese Individuals(BioBank Japan genotype data)

  This reference panel was constructed using whole genome sequencing data from 3,256 Japanese individuals and the 1000 Genomes Project. It provides high accuracy and utility in analyzing genetic polymorphisms, while also reflecting the genetic diversity specific to the Japanese population. This dataset is expected to contribute to the advancement of genetic research and personalized medicine.

  Study JGAS000746

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000709

• An epidemiological study examining the relationship among food, health, and genome

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 962 healthy Japanese. We analyzed the Ebetsu cohort and some participants living in Tokyo. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome and metabolome of feces and blood were analyzed.

  Study JGAS000678

• Whole-genome-sequencing and Whole-exome-sequencing in Myopathy

  To identify the genetic cause and modifiers of Myopathy, we performed Whole-genome-sequencing and Whole-exome-sequencing of Myopathy patients.

  Study JGAS000365

• Whole-exome-sequencing in Frontotemporal dementia (FTD)

  To identify the genetic cause and modifiers of Frontotemporal dementia (FTD), we performed Whole-exome-sequencing of FTD patients.

  Study JGAS000374

• Whole-exome-sequencing and Whole-genome-sequencing and RNA-sequencing in Familial amyotrophic lateral sclerosis (ALS)

  To identify the genetic cause and modifiers of Familial amyotrophic lateral sclerosis (ALS), we performed Whole-exome-sequencing and Whole-genome-sequencing and RNA-sequencing of Familial amyotrophic lateral sclerosis (ALS) patients.

  Study JGAS000358

• Whole-genome-sequencing and Whole-exome-sequencing in Spastic paraplegia

  To identify the genetic cause and modifiers of Spastic paraplegia, we performed Whole-genome-sequencing and Whole-exome-sequencing of Spastic paraplegia patients.

  Study JGAS000494

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established a kind of lung cancer tumoroids derived from a mucus-producing solid pulmonary adenocarcinoma patient. We performed whole exome sequencing and RNA sequencing to analyze genetic background of the tumoroids.

  Study JGAS000664

• RNA-seq data of bone marrow CD34-positive cells from 57 patients with myelodysplastic syndromes (MDS) and 5 healthy individuals (62 participants in total)

  Genetic mutations in hematopoietic neoplasms, seen in disease-specific and non-specific ways, are key drivers in pathogenesis. Typically, these mutations alone don't cause neoplasms; rather, multiple mutations or breakdowns in regulatory mechanisms occur, progressing the disease through stages. Genetic mutation patterns vary even within subtypes, suggesting shared gene expression abnormalities from different mutations may drive neoplasm development. Identifying these "common factors" is vital for effective molecular-targeted therapy development. Our study aims to elucidate neoplasm pathogenesis by analyzing patient genetic abnormalities, pinpointing "common factors" in each subtype for novel targeted therapy development.

  Study JGAS000724

• Phenotype and genotype correlation analysis in tuberous sclerosis complex

  To elucidate the genetic clues of the related clinical manifestations, whole exome sequencing analysis was performed in 163 of the patients with TSC and compared the severity of the symptoms.

  Study JGAS000688

• Amplicon sequencing of melanoma samples

  The types of biomarkers for skin tumors have been 1) biochemical markers in blood, urine, and body fluid, 2) histopathological markers, 3) genetic examination of tumor tissue, 4) tumor-susceptibility assessed by germ_x0002_line genetic examination. Biomarkers in a blood are frequently used in the treatment of cutaneous malignancies, but are not suitable for early detection of malignancies. Research on circulating tumor cells, cell free DNA, exosomes has been promoted in recent years, but clinical application is halfway. Based on these circumstances, the purpose of this study is to search for biomarkers for diagnosis, therapeutic effect, and follow-up of skin tumors, and to verify their usefulness.

  Study JGAS000351

• Comprehensive survey for the construction of an integrated database of food, gut microbiome, and health information (the "Sukoyaka Health Survey")

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 59 healthy Japanese. We analyzed some participants living in Nagasaki. Shotgun metagenomic sequencing of fecal microbiome were analyzed.

  Study JGAS000681

• Exome analysis of cardiomyopathy patients with DSG2 variants

  This research aims to identify genetic background of cardiomyopathy patients with DSG2 pathogenic variants by exome analysis.

  Study JGAS000565

• Comprehensive survey for the construction of an integrated database of food, gut microbiome, and health information (the "Sukoyaka Health Survey") A data collection study exploring the relationship between the gut microbiome, food, health, and the genome.

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 51 healthy Japanese. We analyzed some participants living in Nagahama. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome were analyzed.

  Study JGAS000680

• Chromatin accessibility in stem cells unveils progressive transcriptional reprogramming in myelodysplastic syndrome

  Myelodysplastic syndromes (MDS) originate from hematopoietic stem cell (HSC) clones with acquired gene mutations/deletions. However, our knowledge on the epigenetic properties of MDS stem cells are limited. Here, we examined chromatin accessibility of MDS stem cells. Chromatin accessibility profiles of MDS stem cells represented the disease status better than progenitor cells and unveiled the process of stem cell reprograming during disease progression. Characterization of differentially accessible regions (DARs) revealed that MDS stem cells acquire progenitor-like chromatin accessibility with disease progression, resulting in imprecise stem-progenitor hierarchy. Profiling of transcriptional factor binding motifs at DARs revealed precocious inactivation and activation of HSC and myeloid transcriptional networks, respectively, in MDS stem cells. Increased chromatin accessibility at CEBP target sites well represented the myeloid reprograming of MDS stem cells and stratified MDS into distinct subgroups. Newly developed "Progenitor scores" based on chromatin accessibility well stratified the disease status and correlated with prognosis. These results highlight that the chromatin properties of MDS stem cells define the cell-autonomous behavior of MDS and disease progression.

  Study JGAS000718

• Amplicon sequencing of duodenal adenoma

  The aim of this study is to analyze the methylation and mutation status of non-ampullary duodenal lesions in order to detect the genetic changes for predicting the progression to adenocarcinomas.

  Study JGAS000352

• Deciphering molecular mechanisms underlying hematological malignancies and development of novel therapeutic approaches

  We aim to identify epigenomic features dysregulated in hematological malignancies through epigenetic analyses of hematological malignant cells. We also perform RNA sequencing to profile tumor cell-specific transcriptomes and target gene sequencing to profile somatic gene mutations in tumor cells. Regarding identified epigenomic abnormalities, we perform further analysis to determine whether they could be good candidates to translate into therapy development. To this end, we will modulate the activity of targets by using their activators and inhibitors in vitro and establish xenograft mouse models of hematological malignancies and manipulate their activity in vivo. Through these studies, we aim to develop new therapeutic agents or modalities that lead to improved patients��� prognosis.

  Study JGAS000603

• Analysis of genes associated with autistic spectrum disorder, schizophrenia, and bipolar disorder.

  Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASD-associated genetic variants and individual ASD traits. We performed case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism) and 36 with typical development.

  Study JGAS000731

• Whole genome sequencing of human induced pluripotent stem cells derived from 5 type I cyctic biliary atresia patients

  We have successfully generated a panel of human induced pluripotent stem cells (hiPSCs) from five Japanese patients carrying type I cystic biliary atresia (BA). These hiPSC lines have exhibited characteristics of self-renewal and pluripotency. These cells held normal karyotypes mostly, but one of them carried hemizygous deletions, of which clinical significance is unknown yet. Whole genome sequence analysis indicated that some of the mutations or single nucleotide polymorphisms (SNPs) commonly found in these patients are related to hepatobiliary abnormality. Given the limited understanding of the molecular pathogenesis of cystic BA, attributed to unknown factors of genetic and environmental causes, these cellular resources will be instrumental in replicating disease phenotypes and in the advancement of novel therapies for this condition.

  Study JGAS000765

• Comprehensive survey for the construction of an integrated database of food, gut microbiome, and health information (the "Sukoyaka Health Survey"). A study on the relationship between food and health and genetic background.

  We conducted a cohort-based study to investigate the association between the genetic background and diet/lifestyle in 50 healthy Japanese. We analyzed some participants living in Miyazaki. The SNP array (Japonica Array v2) was used for genotyping. Shotgun metagenomic sequencing of fecal microbiome and metabolome of feces and blood were analyzed.

  Study JGAS000679

• Multi-omic profiling of patient-derived pancreatic tumor organoids

  We conducted multi-omic profiling of patient-derived pancreatic cancer organoids and genetically engineered normal pancreas organoids.

  Study JGAS000719

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established three kinds of lung cancer tumoroids derived from three different pulmonary large cell neuroendocrine carcinoma patients. We performed whole exome sequencing to analyze genetic background of these kinds of tumoroids.

  Study JGAS000641

• Exome analysis of cardiomyopathy patients with TNNT2 variant

  This research aims to identify genetic background of cardiomyopathy patients with TNNT2 pathogenic variants by exome analysis.

  Study JGAS000567

• Unraveling the heterogeneity of multiple myeloma identifies therapy resistant subpopulation with vulnerability to the splicing pathway intervention

  Intra-tumor heterogeneity underlies the therapy resistance of multiple myeloma (MM). However, its details remain unknown. Here, we performed single-cell RNA sequencing coupled with VDJ targeted sequencing on highly purified bone marrow lineage marker-negative CD38+ MM cells from patients at diagnosis and in remission. This approach successfully subdivided MM cells into distinct clusters, unraveling their heterogeneity and plasticity on the axis of cell surface CD138 expression. Notably, unique clusters were identified in the minor CD138-negative population that resisted therapies. CRISPR/Cas9 screening of upregulated genes in the resistant population identified their vulnerability to the splicing pathway inhibition, among which RNA-binding protein 39 (RBM39) appeared to be overexpressed in the resistant population and involved in aberrant splicing. Genetic and pharmacological inhibition of RBM39 exerted a profound synthetic lethal effect on them. Our results unveil an uncharacterized subpopulation associated with therapy resistance and provide a novel therapeutic strategy targeting the splicing pathway in MM.

  Study JGAS000723

• Whole-genome-sequencing, Whole-exome-sequencing and RNA-sequencing in Sporadic ALS

  To identify the genetic cause and modifiers of Sporadic ALS, we performed Whole-genome-sequencing, Whole-exome-sequencing and RNA-sequencing of Sporadic ALS patients.

  Study JGAS000393

• LEF1 knockdown effects on human T cell transcriptome and chromatin accessibility profiles.

  LEF1 (Lymphoid Enhancer-Binding Factor 1) is a key transcription factor in T cell development and function, and its dysregulation has been implicated in various immune-related disorders. This study aimed to comprehensively characterize the transcriptional and epigenetic changes induced by LEF1 knockdown in human T cells. CD3+ T cells isolated from three healthy donors were transfected with either LEF1-specific siRNA or control siRNA, followed by activation with CD3/CD28 Dynabeads and culture in IL-2-containing media. Cells were harvested at 24, 48 and 72 hours post-transfection for multi-omics analysis including bulk RNA-seq, bulk ATAC-seq, single-cell CITE-seq (For CITE-seq, 48 and 72 hours only). This dataset provides insights into LEF1-dependent gene regulatory networks and chromatin accessibility patterns in activated human T cells, contributing to our understanding of T cell biology and potential therapeutic targets. This dataset is part of a comprehensive study investigating functional roles of risk polymorphisms in autoimmune diseases, particularly focusing on the rs58107865 variant at the LEF1 locus.

  Study JGAS000818

• Singel-cell RNA sequencing and CUT&RUN sequencing of human RUNX2-deficient osteoblasts

  Runx2 is a master regulator of bone formation, and its dysfunction causes cleidocranial dysplasia (CCD) in humans. When iPS cells were generated from patients with CCD and Runx2-deficient iPS cells were generated using gene-editing techniques, abnormal laminopathy-like nuclei were observed. Runx2-deficient cells showed reduced Lamin A/C expression, but not protein levels. However, in Runx2-deficient cells, both the gene expression and protein levels of Nesprin-1 were reduced, perinuclear actin fibers were sparser, and nuclear stiffness was reduced. Forced expression of Lamin A/C increased nuclear stiffness but did not improve nuclear morphology. In contrast, the induction of Nesprin-1 expression alone normalized nuclear stiffness and restored nuclear morphology and perinuclear actin distribution. In Runx2-null cells, mechanical stress-induced phosphorylation of emerin was not observed. In contrast, forced expression of nesprin-1 in Runx2-null cells resulted in phosphorylation of emerin, indicating the restoration of intracellular tension. These observations were confirmed by atomic force microscopy. Therefore, the intracellular tension was inferred to pull the nuclear membrane into its normal shape. CUT&RUN assay and single RNA-seq analysis showed that an aberrant nuclear membrane caused loss of nuclear lamina gene regulation machinery, making the progression of normal osteogenic differentiation impossible; however, supplementation with Nesprin-1 restored gene regulation mechanisms and promoted pre-osteoblast formation with normal nuclear morphology. Nesprin-1 expression induced by Runx2 is essential for epigenetic regulation of the nuclear lamina. We propose CCD as a new type of laminopathy involving defective expression of Nesprin-1 regulated by Runx2.

  Study JGAS000663

• Genetic and epigenetic analysis of individuals with porokeratosis

  We performed genome sequencing���including whole-exome sequencing (WES), whole-genome sequencing (WGS), long-read WGS, and amplicon-seq���along with SNP array, methylation array, and RNA-seq on samples of epidermis (both lesion and non-lesion), peripheral blood, and/or cultured keratinocytes from individuals with porokeratosis.

  Study JGAS000684

• In vitro reconstitution of epigenetic reprogramming in the human germ line

  Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>1010-fold). Strikingly, bone morphogenetic protein (BMP) signalling is a key driver of these processes: BMP-driven hPGCLC differentiation involves an attenuation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation. On the other hand, hPGCLCs deficient in tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells, differentiate into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters; these cells fail to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated. Our study elucidates the framework of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.

  Study JGAS000690

• Application of organoid culture system of human gastrointestinal and thoracic cancer in genome medicine

  In order to establish preclinical models, we have established a kind of lung cancer tumoroids derived from a mucus-producing solid pulmonary adenocarcinoma patient. We performed whole exome sequencing and RNA sequencing to analyze genetic background of the tumoroids.

  Study JGAS000653

• Exome analysis of cardiomyopathy patients with PKP2 variants

  This research aims to identify genetic background of cardiomyopathy patients with PKP2 pathogenic variants by exome analysis.

  Study JGAS000566

• Whole-exome-sequencing in Charcot-Marie-Tooth disease (CMT)

  To identify the genetic cause and modifiers of Charcot-Marie-Tooth disease (CMT), we performed Whole-exome-sequencing of CMT patients.

  Study JGAS000337