14662 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

in 50.71 milliseconds.

• (Epi)genetic Risk Architectures of Opioid-Dependent Brain

  With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one of the most pressing public health crises in recent US history. One-fifth of individuals who try heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated 60% heritability, only somewhat less than schizophrenia (80%) which has recently seen substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA heritability unexplained. The proposed study takes a novel, integrated "omics-based" strategy to investigate the molecular basis of OA and uncover both genetic and epigenetic factors associated with opioid addiction. The premise for our approach is founded on studies from our labs, and others, implicating regulatory variation in common traits and diseases, including those associated with complex brain phenotypes like addiction. We have collected the largest known cohort of postmortem brains from addicts who overdosed on opioids, along with matched control brains from non-users. From both cases and control specimens, we will isolate cells from 2 regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC) and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify regulatory elements that distinguish cases from controls and define the opioid addiction phenotype. The regulatory differences will be connected to their gene targets through high resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify genetic variants that underlie differences in transcript levels between cases and controls. Aim 3 leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that SNPs in regions associated with chromatin and expression differences between cases and controls define novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is the most powerful component of the proposed study: identifying regulatory pathways that generate, not only phenotype associations, but hypothesized mechanisms for those associations which can be the focus of new opioid addiction prevention and treatment development.

  Study phs002724

• Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES)

  The T2D-GENES/GoT2D 13K exome sequencing study includes ~13,000 samples, half T2D cases and half T2D controls, from five ancestries (~5K Europeans, ~2K each of African-American, East-Asian, South-Asian, and Hispanic). Samples underwent deep exome sequencing, with SNVs and INDEls called according to GATK best practices; variant sites were then filtered according to the GATK best practices, and then samples and variants underwent further filtering based on aggregate genotype quality as described in Fuchsberger et al. (e.g. low call rate, excess heterozygosity for samples, low call rate or coverage for variants). Please note that one of the samples in the T2D-GENES vcf does not have phenotype data.

  Dataset EGAD00001002246

• Whole genome sequencing of multiple myeloma patient samples.

  Tumor (CD138+ plasma cells) and non-tumor (peripheral blood white cells or stem cell harvest) DNA from patients with a plasma cell dyscrasias were sequenced. Whole genome sequencing using high molecular weight DNA was performed using the 10X Genomics Chromium platform on either a HiSeq4000 or NovaSeq (Illumina) using 100 to 150 bp paired-end reads. The dataset consists of 111 patients, and 223 samples in total (matched tumor and control per patient; one patient had 2 tumor samples sequenced). Diseases consisted of 2 MGUS patients, 8 SMM patients, 91 newly diagnosed myeloma patients, 1 previously treated patient, 4 relapsed MM patients, and 5 PCL patients. Paired RNA-seq data are available for 81 of the samples under study EGAS00001003411.

  Dataset EGAD00001004452

• NHLBI TOPMed: Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE)

  Started in 2007, the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) is one of the largest asthma cohort studies in the United States. Its overarching goal is to elucidate the genetic underpinnings of asthma and asthma medication treatment response. The cohort was recruited from a large health care system serving southeast Michigan and the Detroit metropolitan area, and the participants broadly represent the demographic and socioeconomic diversity of the region. Control participants (i.e., patients without a diagnosis with asthma) were recruited from the same health system and geographic region. By virtue of their health system enrollment, both asthma case and control patients have longitudinal clinical information which was routinely collected as part of their care. Both case and control patients underwent at detailed evaluation at the time of enrollment which included lung function testing and bronchodilator response. The SAPPHIRE cohort is a member of the Asthma Translational Genomics Collaborative (ATGC). The latter was selected for whole genome sequencing in Phase 3 of the National Heart Lung and Blood Institute's TOPMed Program. The SAPPHIRE sample selected for sequencing includes African American and/or Latino individuals with and without asthma.

  Study phs001467

• Japan PBC-GWAS Haplotype Study

  Primary biliary cholangitis (PBC) susceptibility loci have largely been discovered through single SNP association testing. In this study, we report genic haplotype patterns associated with PBC risk genome-wide in two Japanese cohorts. Among the 74 genic PBC risk haplotype candidates we detected with a novel methodological approach in a discovery cohort of 1,937 Japanese, nearly two-thirds were replicated (49 haplotypes, Bonferroni-corrected P<6.8x10-4) in an independent Japanese cohort (N=949). Along with corroborating known PBC-associated loci (TNFSF15, HLA-DRA), risk haplotypes may potentially model cis-interactions that regulate gene expression. For example, one replicated haplotype association (9q32-9q33.1, OR=1.7, P=3.0x10-21) consists of intergenic SNPs outside of the human leukocyte antigen (HLA) region that overlap regulatory histone mark peaks in liver and blood cells, and are significantly associated with TNFSF8 expression in whole blood. We also replicated a novel haplotype association involving non-HLA SNPs mapped to UMAD1 (7p21.3; OR=15.2, P=3.9x10-9) that overlap enhancer peaks in liver and memory Th cells. Our analysis demonstrates the utility of haplotype association analyses in discovering and characterizing PBC susceptibility loci.

  Study EGAS00001002915

• Study of Addiction: Genetics and Environment (SAGE)

  This study is part of the Gene Environment Association Studies initiative (GENEVA) funded by the National Human Genome Research Institute. The overarching goal is to identify novel genetic factors that contribute to addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent. The focus of this proposal is a case-control design of unrelated individuals for a genetic association study of addiction. Cases are defined as individuals with DSM-IV alcohol dependence (lifetime) and potentially other illicit drug dependence. In addition to the categorical diagnosis, we have data on ordinal measurements of number of DSM-IV symptoms for alcohol, nicotine, marijuana, cocaine, opiates and other drugs so that we will able to construct quantitative measurements of addiction severity over a wide range of substances. Controls are defined as individuals who have been exposed to alcohol (and possibly to other drugs), but have never met lifetime diagnosis for alcohol dependence or dependence on other illicit substances. Analyses that include refinement of the phenotype and incorporation of important demographic and environmental factors into association studies will be pursued. Cases and controls were selected from three large, complementary datasets: the Collaborative Study on the Genetics of Alcoholism (COGA), the Family Study of Cocaine Dependence (FSCD), and the Collaborative Genetic Study of Nicotine Dependence (COGEND). COGA: COGA was initiated in 1989 and is a large-scale family study that has had as its primary aim the identification of genes that contribute to alcoholism susceptibility and related characteristics. COGA is funded through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Subjects were recruited from 7 sites across the U.S. Alcohol dependent probands were recruited from treatment facilities and assessed by personal interview. 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 the alcohol dependent probands. Assessment involved a comprehensive 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. Families with three or more first-degree relatives who were alcohol dependent were invited for more extensive testing, including neurophysiology evaluations (ERPs and EEGs) and a battery of neuropsychological assessments. Blood was obtained for genetic studies. Institutional Review Boards at all sites approved the protocols, including sharing in the NIAAA national repository. COGA has four Co-Principal Investigators Bernice Porjesz, Victor Hesselbrock, Howard Edenberg, and Laura Bierut. COGA includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-investigators are: University of Connecticut (Victor Hesselbrock); Indiana University (Howard Edenberg, John Nurnberger, Jr., Tatiana Foroud); University of Iowa (Samuel Kuperman); SUNY Downstate (Bernice Porjesz); Washington University in St. Louis (Laura Bierut, Alison Goate, John Rice); University of California at San Diego (Marc Schuckit); Howard University (Robert Taylor); Rutgers University (Jay Tischfield); Southwest Foundation (Laura Almasy). Q. Max Guo serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Family Study of Cocaine Dependence (FSCD): This project was initiated in 2000 as a case-control family study of cocaine dependence funded through the National Institute on Drug Abuse (NIDA; PI: Laura Bierut). The primary goal was to increase the understanding of the familial and non-familial antecedents and consequences of cocaine dependence. Cocaine dependent individuals were systematically recruited from chemical dependency treatment units (both public and private; residential and outpatient) in the greater St. Louis metropolitan area. Community based control subjects were identified through a Missouri Driver's License Registry (maintained at Washington University for research purposes) and matched by age, race, gender, and residential zip code. As a supplement to this project, blood samples were collected for future genetic analysis and were included in the NIDA Genetics Consortium. Phenotypic data, DNA, and cell lines are in the NIDA Center for Genetics Studies. Collaborative Genetic Study of Nicotine Dependence (COGEND): COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design is a community based case-control family study. All subjects were recruited from Detroit and St. Louis. Nicotine dependent cases and non-dependent smoking controls were identified and recruited. In addition, one sibling for each case and control subject was recruited in a subset of the sample. Over 56,000 subjects aged 25-44 years were screened by telephone, over 3,100 subjects were personally interviewed, and over 2,900 donated blood samples for genetic studies. All three studies (COGA, COGEND, FSCD) include measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, educational attainment, religious participation, and family structure. Other important covariates and/or potential moderators of genetic effects include comorbid addictions and age at initiation of use for cigarettes, alcohol and drugs. The assessments also include measures of various life stressors, such as physical and sexual abuse, which have been implicated in gene-environment interactions for several disorders. Coding for both individual variables and indices has been standardized across studies. All subjects were assessed in person by trained research assistants. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR), was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease"(HHSN268200782096C). Note for Publications Related to Study: The Study of Addiction: Genetics and Environment (SAGE) has not yet generated publications. Below is a listing of publications related to the three studies from which the SAGE sample was selected. COGA has over 228 publications listed at www.niaaagenetics.org This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to addiction through a large-scale genome-wide association study of DSM-IV alcohol dependent (and frequently illicit drug dependent) cases and non-dependent, unrelated control subjects of European and African American descent. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000092

• Whole_genome_sequencing_of_100_DDD_trios_with_suspected_noncoding_causal_mutations

  We would like to whole-genome sequence 100 trios (300 individuals) from the DDD project in which we suspect the proband has a pathogenic noncoding mutation, to 30X coverage. These have been carefully selected to maximise the chances of finding pathogenic noncoding mutations. Specifically, we have selected probands who have no likely causal mutation within the coding region but who have a heterozygous loss-of-function mutation inherited from one parent in a known recessive developmental disorder gene, and whose phenotype is a good match for the typical phenotype caused by recessive variants in that gene. We suspect that these probands may have a heterozygous noncoding mutation on the other allele which reduces expression of the gene so that, together, these two mutations are effectively equivalent to a homozygous loss-of-function mutation. About a quarter of the probands have affected siblings and, if those siblings have been exome sequenced, we have checked that they are identical-by-descent in the region of the gene. We propose to search in the promoter region, intronic and annotated regulatory regions around these genes of interest for rare variants inherited from the other parent (i.e. not the one who transmitted the loss-of-function variant), or de novo variants. If we find such variants, and demonstrate an enrichment of this compound heterozygous LoF noncoding mechanism above that expected by chance, we intend to follow up specific candidates by RNAseq and potentially CRISPR/Cas9 experiments. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002452

• Genetics of Neuropsychiatric and Neurodevelopmental Disorders

  Although schizophrenia is a highly heritable disease, relatively little progress had been made in securely identifying the genetic causes of this disorder, and most instances of schizophrenia in the general population remain unexplained. One avenue of explanation for the genetic basis of schizophrenia, however, has been effectively closed by recent research. Genome-wide association studies (GWAS) have now shown that common variation makes at most a modest contribution to the risk of schizophrenia. At the same time that the role of common variation has been circumscribed by GWAS, however, the analysis of copy number variants that are detectable on a genome-wide scale has revealed and replicated a number of very rare variants that associate with schizophrenia. These rare copy number variants that have been implicated in schizophrenia, however, have one striking feature in common: they are all risk factors for other brain related disorders beyond schizophrenia such as mental retardation, autism and epilepsy. These findings argue that genetic risk factors may confer a highly penetrant vulnerability to neuropsychiatric disorder, which is then further modified by interacting genetic or environmental factors to determine the ultimate manifestation. Most schizophrenia collections that are being studied today, however, have been selected precisely for their homogeneity: including only schizophrenia patients with no comorbidities, or schizophrenia patients with relatives who have schizophrenia but no other neuropsychiatric conditions. These selection criteria are inconsistent with what we now know about the bulk of the genetic differences that have been associated with disease. The central hypothesis of this project is that there are rare genetic variants that strongly elevate the risk of various neuropsychiatric diseases, and that these risk factors can be identified most readily in families segregating multiple neuropsychiatric conditions.

  Study phs000682

• Cell-Free DNA Genomic and Fragmentomic Features for Early Outcome Prediction in Diffuse Large B-Cell Lymphoma

  Purpose: Diffuse large B-cell lymphoma (DLBCL) patients need an accurate and early risk stratification strategy as prompt therapy escalation may improve outcome. Patients and methods: We evaluated cell free DNA (cfDNA) genomic and fragmentomic features in 190 patients with large B-cell lymphoma from more than 40 hospitals in the Benelux using Whole Genome Sequencing (WGS). We defined a new metric called ACT score (Aberrations, Contribution of short fragments, Terminal motif analyses) by combining four cfDNA signals and evaluated its performance to predict end-of-treatment (EOT) response and survival. Results: Individual cfDNA features and ACT score were altered per EOT response after one cycle of treatment (T1). The ACT score at T1 outperformed all individual cfDNA features in predicting EOT response (AUC = 0.74). Patients with a positive ACT score had an inferior outcome compared to ACT score negative patients [progression-free survival (PFS): HR 5.0 (95% CI 3.1-8.2), log-rank test, p < 0.0001) and overall survival (OS): HR 6.5 (95% CI 3.5-12.2), log-rank test, p < 0.0001]. The 2-year PFS in ACT score positive and negative patients were 29.8% and 78.1%, respectively. The prognostic value of the ACT score is independent of the International Prognostic Index and interim imaging. Conclusions: ACT score computed from a single plasma sample collected after one cycle of treatment can predict clinical outcome. This low-cost and easy-to-interpret test does not require tissue biopsies or a priori knowledge of mutations and has the potential to aid patient selection in interventional clinical trials and risk-adapted treatment strategies.

  Study EGAS50000000412

• Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer

  Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNA variants in >48,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) are detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells and are generally absent from basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs were not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium including from high risk women, link early stage CNAs to clonally expanded tumor genomes .

  Study EGAS00001007716

• Distinct evolutionary trajectories of primary high grade serous ovarian cancers revealed through spatial mutational profiling

  High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to emergence of treatment-resistant sub-clones. We sought to measure the degree of genomic diversity within primary, untreated HGSC to examine the natural state of tumor evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on thirty-one spatially and temporally separated HGSC tumor specimens (six patients) including ovarian masses, distant metastases, and fallopian tube lesions. We found widespread intra-tumoral variation in mutation, copy number, and gene expression profiles, with key driver alterations in genes present in only a subset of samples (e.g. PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range: 10.2% to 91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology with common etiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating diversity arises at early stages of tumorigenesis. Our results reveal that HGSC exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug resistance mechanisms.

  Study EGAS00001000547

• Multi-Layered Molecular Profiling Informs the Diagnosis and Targeted Therapy of Desmoplastic Small Round Cell Tumor

  Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft tissue sarcoma with dismal prognosis and limited therapeutic options. Here, we identified individual therapeutic targets in a cohort of 30 DSRCT patients by use of multilayered molecular profiling (genomic, transcriptomic, and (phospho-)proteomic analyses) within the DKFZ NCT DKTK MASTER program. 28 of the 30 patients received at least one personalized treatment recommendation. In line with the observation that DSRCTs are an entity with a low mutational load, most of the treatment recommendations were based on target gene or -protein expression. 13 patients received a recommended therapy, resulting in four partial responses, four stable diseases, and five progressive diseases. Eight of 13 patients received the multi tyrosine kinase inhibitor pazopanib, with mixed response. Based on high ERBB2 expression levels, two patients received the antibody drug conjugate trastuzumab deruxtecan (T-DXd), showed exceptional, long-lasting responses and are currently (8/2024) still on treatment and progression-free. We detected high ERBB2 protein expression in all DSRCT samples with proteome data (n = 9), which suggests that ERBB2 may be a particularly useful therapeutic target for DSRCT patients. For one of the two exceptional responders we did not detect a substantial ERBB2/HER2 overexpression, which may indicate that T-DXd could also be efficacious in DSRCT patients with low levels of HER2, as also described for breast cancer patients. In conclusion, multi-omic molecular profiling revealed personalized therapeutic targets in patients with DSRCT with HER2 targeting, with T-DXd as a promising therapeutic option for this ultra-rare and difficult-to-treat tumor entity.

  Study EGAS00001007934

• Single_cell_measurements_to_characterise_B_cell_repopulation_in_SLE_after_rituximab_therapy__a_pilot_study

  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by autoantibodies against DNA and nuclear proteins. Kidney involvement (lupus nephritis) is one of the most serious manifestations and is the leading determinant of long-term prognosis. Therapies targeting B cells (e.g. rituximab) are used in the treatment of severe lupus, including lupus nephritis. Rituximab is a monoclonal antibody that targets the CD20 surface protein on the surface of B cells. Following rituximab treatment, there is near complete depletion of B cells in peripheral blood. Peripheral blood B cells slowly return over a period of months. The speed of repopulation varies but typically B cells have returned to baseline levels between 9 and 12 months post rituximab therapy. Return of B cells may be associated with increased disease activity, but this is not always the case. For example, some patients remain in clinical remission for several years following one cycle of rituximab, despite B cell repopulation, whilst others relapse as soon as the B cell number reaches the normal range. The reasons for the different response remain unclear. The B cell subpopulations that return following B cell depleting therapy have been previously studied using flow cytometry but have never been characterised using single cell -omic technologies and thus no data on their molecular signatures are available. Previous studies have shown that naïve B cells were the predominant repopulating B-cells, indicating de novo production of B cells. Obtaining an integrated understanding of the molecular programs of these cells at the single cell level will enhance our ability to predict disease outcome, to identify patients with poorer B-cell drug responses, understand disease heterogeneity and design more effective B-cell targeted therapies approach.

  Study EGAS00001006798

• Atherosclerosis Risk in Communities Study (ARIC-BioLINCC)

  Data Access NOTE:Please refer to the &#8220;Authorized Access&#8221; section below for information about how access to the data from this accession differs from many other dbGaP accessions. At present, the ARIC sIRB has determined that ARIC data cannot be shared with for-profit entities.Related Studies Other ARIC data available include: Imaging studies (ARIC-Imaging), Genetics and genomics (ARIC, phs000280.v8.p2), Collaborative Cohort of Cohorts for COVID-19 Research (C4R): ARIC (phs002988.v1.p1), and as a component of the Sleep Heart Health Study (SHHS-BioLINCC, phs003637.v1.p1). Available Data Data available for request include ARIC v1-v8 examination cycles, collated annual follow-up communication data for contact years 2-32, and follow-up for mortality, heart disease, and stroke events through 2019. Also included are data from ancillary studies. Objectives The objectives of ARIC are to: 1) investigate associations of factors, including those not previously measured in cohort studies, with prevalence of atherosclerosis and incidence of CHD, clinical stroke and other cardiovascular diseases; and 2) measure cardiovascular disease occurrence and trends and relate these to community levels of, and changes in, risk factors, medical care and atherosclerosis. Background At the time of project initiation, the NHLBI had long recognized the need for longitudinal studies to identify the biochemical and physiological markers and specific environmental factors which place individuals at high risk for the major atherosclerosis diseases. The development of reliable ultrasound examination of peripheral arteries enhanced the expected benefit of such studies. Community surveillance planning began for ARIC in response to recommendations of the 1978 NHLBI Workshop on the Decline in CHD Mortality and has been extended in its purpose to evaluate the large geographic differences in U.S. mortality. Participants Black and white men and women, age 45-64 at entry; sample size: 15,792. Design ARIC is a large-scale, long-term prospective study that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women from four geographically diverse communities. The project has two components: community surveillance of morbidity and mortality; and repeated examinations of a representative cohort of men and women in each community. The community surveillance involves abstracting hospital records and death certificates and investigating out-of-hospital deaths. The representative cohorts include approximately 4,000 persons from each community. Community surveillance data includes detailed hospital record abstraction, ECG tracings, and event adjudication. Data from out-of-hospital events in the community include physician, informant, and coroner questionnaires as well as death certificate data and event adjudication. Community surveillance ended in 2014.Cohort participants were examined four times at three year intervals between 1987 and 1998, and have been continuously contacted annually to update their medical histories. Atherosclerosis was measured by carotid ultrasonography. Risk factors studied include: blood lipids, lipoprotein cholesterols, and apolipoproteins; plasma hemostatic factors; blood chemistries and hematology; sitting, supine and standing blood pressures; anthropometry; fasting blood glucose and insulin levels; ECG findings; cigarette and alcohol use; physical activity levels; dietary aspects; and family history. Clinic visits were restarted in 2011 with ARIC visit 5.

  Study phs003738

• Oxford Nanopore WGS

  A total of 20 individuals, were analyzed using Oxford Nanopore Technologies long-read sequencing. Each individual was sequenced on one PromethION flow-cell, providing approximately 25-30X coverage of the genome. The data is deposited as nanopore BAM files with methylation information included.

  Dataset EGAD50000000573

• LRS - episignature samples

  This dataset contains 22 long-read WGS fastq.gz files sequenced ONT PromethION. In total the dataset includes 20 individuals, for all of them sequencing starting from blood was performed, and for one of the samples sequencing from urine and from the buccal swab was also included. In all the samples methylation calls are included in the fastq file.

  Dataset EGAD50000001000

• LuCaP cell line RNA-seq

  RNA-seq of LuCaP 189.4 cell line. Treatment with DCC DMSO (n=3 replicates) or 1nm R1881 (n=3 replicates). All 6 samples were sequenced using cDNA oligo-dT using paired-end reads on Illumina NovaSeq 6000. Each sample has 2 fastq files, one for the forward and reverse read, respectively.

  Dataset EGAD50000001344

• WGS data of paediatric B-other B cell acute lymphoblastic leukemia (set6)

  The dataset includes FASTQ and CRAM files from diagnostic and matched remission (control) samples of one B-other ALL patients (ALLK-138). Sequencing library was made using Novogene NGS DNA Library Prep Set. Both diagnostic (90x) and remission (30x) samples were sequenced using NovaSeqX Plus.

  Dataset EGAD50000002161

• Exome Sequencing of Spanish Patients with rare genetic diseases.

  Whole Exome sequencing of a set of Spanish patients suffering rare genetic diseases. The set consists of 3 patients, two were diagnosed with Aniridia (ANI-0006 and ANI-0023) and another one was diagnosed with Retinitis Pigmentosa (RP-0247).

  Dataset EGAD00001005498

• MCO colorectal cancer genomics at UNSW

  This dataset contains DNA sequencing data from 95 colorectal cancer and matched-normal samples. The dataset contains targeted deep sequencing of selected regulatory elements in 95 cancer and matched-normal samples, and data for one sample that was additionally whole-genome sequenced (cancer and matched-normal).

  Dataset EGAD00001004582

• CTCF ChIP-sequencing data for Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma

  This dataset contains CTCF ChIP-sequencing data from seven samples (six tumor samples and one tumor derived cell line). Following library amplification, DNA fragments were sequenced using Illumina HiSeq 2000 paired-end sequencing resulting in 14 FASTQ files.

  Dataset EGAD00001008806

• Whole Exome Sequencing of a Chinese Cataract Girl

  Whole exome sequencing of a Chinese girl with congenital cataract. The dataset contains one sample with two fastq files. The novel PAX6 mutation (c.221G&gt;A) is associated with congenital cataract, and the WFS1 mutation (c.2070_2079del) interactively aggravates this process.

  Dataset EGAD00001008267

• Exome sequencing of synchronous colorectal cancers

  The data consists of 47 exome-sequenced synchronous colorectal cancers from 23 patients. The exomes of corresponding normal samples were used to remove germline variants. All patients are Finnish (white Caucasian). All except one patient (sync_11 who belongs to a LS family) were assumed sporadic. The sequence data was produced with Illumina HiSeq 4000.

  Dataset EGAD00001004884

• Epigenetic Changes in Immune Response and Oncogenesis Related Genes Caused by Heavy Metal Long-Term Exposure

  Our study investigated methylation changes in CpG islands located in immune response and oncogenesis related genes in humans induced by long-term environmental heavy metal exposure. We assessed the methylation levels of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5 and IGF2/H19 genes by targeted bisulfite sequencing (target enrichment by 48.48 Access Array Integrated Fluidic Circuit (Fluidigm, USA) in a cohort of 40 subjects living near a metal mining area (the Kapan mining region, Armenia) and 40 unexposed subjects. We performed linear regression on our data to find differentially methylated positions with adjustment for gender, age, BMI class, smoking, and plasma concentrations of 21 essential and non-essential metals detected by ICP-MS. Our study showed hypomethylation of five CpG sites in the NFKB1 promoter region in the exposed group. According to our findings, the methylation changes of CpG sites in NFKB1, CDKN2A, IGF2 and ESR1 genes are associated with multiple and specific metal exposures. Targeted bisulfite sequencing data obtained for 80 subjects who participated in this study are available through dbGaP. The tables contain information about age, sex, BMI, smoking and exposure status, as well as race and ethnicity of the study participants.

  Study phs003392

• Prevention and Early Treatment of Acute Lung Injury Network - Vitamin D to Improve Outcomes by Leveraging Early Treatment (PETAL VIOLET-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL VIOLET include Plasma and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Specimens may not be used to produce commercial products.Objectives: To evaluate the effect of short-term vitamin D supplementation on mortality among critically ill patients with a vitamin D deficiency.Background: Observational data indicate that vitamin D deficiency is common among critically ill patients and constitutes a potentially modifiable risk factor associated with longer lengths of stay in the hospital and intensive care unit (ICU), lung and other organ injury, prolonged mechanical ventilation, and death. In a previous phase 2 trial, vitamin D supplementation administered to vitamin D-deficient, critically ill patients was associated with lower observed mortality than placebo at 28 days and at 6 months. Because of the need for a larger, phase 3 trial, the PETAL-VIOLET study was initiated to determine if early administration of high-dose vitamin D3 would reduce all-cause mortality among critically ill patients with a vitamin D deficiency.Participants: 1360 patients underwent randomization, 690 were assigned to the vitamin D group and 668 were assigned to the placebo group. Of the 1078 patients confirmed to have a vitamin D deficiency by liquid chromatography-tandem mass spectrometry (LC-MS-MS), 538 had been assigned to the vitamin D group and 540 had been assigned to the placebo group.Design: PETAL-VIOLET was a multicenter, double-blind, placebo-controlled, phase 3 trial. Patients were enrolled within 12 hours after the clinician's decision to admit the patient to the ICU from the emergency department, hospital ward, operating room, or outside facility. Patients were tested for vitamin D deficiency, with a threshold of plasma 25-hydroxyvitamin D level of less than 20 ng per milliliter. Patients were randomly assigned in a 1:1 ratio, stratified according to site, to receive either a single enteral (administered orally or through a nasogastric or orogastric tube) dose of 540,000 IU of vitamin D3 or matched placebo, in liquid form, administered within 2 hours after randomization.Conclusions: After the first interim analysis, the data and safety monitoring board recommended that the trial be stopped for futility.A single 540,000 IU enteral dose of vitamin D3 administered early during critical illness rapidly corrected vitamin D deficiency but did not provide an advantage over placebo with respect to mortality or other clinically important end points.

  Study phs003879

• Patient Registry for Primary Pulmonary Hypertension (PPH Registry-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 Establish a patient registry to evaluate the natural history, etiology, pathogenesis and treatment of primary pulmonary hypertension. Specific aims included the characterization of the demographic, medical history, family history, physical and laboratory findings of patients at time of diagnosis, and to characterize the survival duration of patients by traits evaluated at diagnosis and by medical interventions. Background There are several known causes of pulmonary hypertension: chronic obstructive pulmonary disease, congenital heart disease, mitral stenosis, left ventricular dysfunction and recurrent pulmonary emboli. Primary Pulmonary Hypertension is a disorder of unknown etiology which is diagnosed only after the known causes of pulmonary hypertension have been eliminated. Prior to the PPH registry, little was known regarding the epidemiology, etiology, natural history or ultimate survival among patients with PPH. In 1973, the WHO met to review the current state of knowledge on PPH and proposed the establishment of a multicenter collaborative study. The NHLBI PPH registry enrolled patients in the registry from 1981 to 1985. Participants Participants were enrolled into the registry from 32 medical centers throughout the US. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of >25 mmHg at rest or 30 mmHg with exercise at catheterization. The diagnosis of primary pulmonary hypertension was only accepted after the following secondary causes of pulmonary hypertension had been excluded: pulmonary hypertension within the first year of life, congenital abnormalities of the heart, lungs, or diaphragm, pulmonary thromboembolic disease, diagnosis of sickle cell anemia, history of intravenous drug abuse, obstructive lung disease, interstitial lung disease, arterial hypoxemia, collagen vascular disease, parasitic disease affecting the lungs, pulmonary artery or valve stenosis, or pulmonary venous hypertension. Baseline and follow-up data collected on participants include demographic characteristics, chest radiograph, pulmonary function tests, lung perfusion scan or pulmonary angiogram, intracardiac left-to-right shunt, pulmonary hemodynamics, as well as a history, physical findings and other laboratory measurements. Participants were followed for approximately 5 years. Conclusions There were 1.7 females for each male in the registry, and females tended to present with more severe symptoms. The mean time from onset of symptoms to diagnosis was 2 years. Right ventricular hypertrophy was found in 87% of participants and right atrial pressure was elevated in 72% of participants. The estimated median survival was 2.8 years with single year survival rates of: 1 year, 68%; 3 years, 48%; and 5 years, 34%. (Ann Intern Med, 1987; 107:216-23, Ann Intern Med, 1991; 115:343-49).

  Study phs004275

• Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts

  MicroRNAs (miRNAs) are regulatory noncoding RNAs that affect the production of a significant fraction of human mRNAs via post-transcriptional regulation. Interindividual variation of the miRNA expression levels is likely to influence the expression of miRNA target genes and may therefore contribute to phenotypic differences in humans, including susceptibility to common disorders. The extent to which miRNA levels are genetically controlled is largely unknown. In this report, we assayed the expression levels of miRNAs in primary fibroblasts from 180 European newborns of the GenCord project and performed association analysis to identify eQTLs (expression quantitative traits loci). We detected robust expression for 121 miRNAs out of 365 interrogated. We have identified significant cis- (10%) and trans- (11%) eQTLs. Furthermore, we detected one genomic locus (rs1522653) that influences the expression levels of five miRNAs, thus unraveling a novel mechanism for coregulation of miRNA expression

  Study EGAS00000000056

• Evolutionary Trajectories of Small Cell Lung Cancer under Therapy

  Small cell lung cancer (SCLC) is one of the deadliest human cancers with a five-years survival rate of less than 7%. The standard of care for extensive-stage SCLC consists of systemic treatment with platinum and etoposide, recently combined with PD-L1 immune checkpoint inhibitors (ICI). SCLC patients show high sensitivity to platinum-based chemotherapy, followed by rapid recurrence, which distinguishes SCLC from most human cancers. Unfortunately, second-line treatment with other chemotherapeutics or immunotherapy is only marginally effective, and patients ultimately succumb to their disease. We performed whole exome sequencing, whole genome sequencing and transcriptome sequencing of multiple tumor regions from 65 patients with SCLC. We determined tumor phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multi-region sequencing of 160 tumors from 65 patients, to thus decipher the evolutionary processes underlying the remarkable sensitivity of small cell lung cancer (SCLC) to chemotherapy.

  Study EGAS50000000169

• ARST17B2-Q Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. While these malignancies display aberrant myogenic differentiation, relatively little is known about genetic susceptibility to RMS, or how genetic variants influence subsequent somatic events and may be used in risk stratification strategies. A small percentage of cases are associated with mutations in TP53 (Li-Fraumeni syndrome), HRAS (Costello syndrome), and PTCH1 (nevoid basal cell carcinoma syndrome/Gorlin syndrome), suggesting the genetic origins of childhood RMS. In spite of this, little work has been done to characterize genetic susceptibility to this malignancy. We plan to leverage samples collected as part of D9902 to conduct one of the largest germline genomic studies of RMS. We anticipate that once genetic associations are identified, researchers can use the information to develop better strategies to detect, treat, and prevent childhood RMS.

  Study phs003192

• IFN-γ and TNF-α drive a CXCL10+ CCL2+ Macrophage Phenotype Expanded in Severe COVID-19 Lungs and Inflammatory Diseases with Tissue Inflammation

  We explored how the human macrophages response to different inflammatory factors, focusing particularly on the effects of antiviral interferons (IFN-&#946; and IFN-&#947;), pro-inflammatory cytokines such as TNF-&#945;, and other mediators like IL-4. Co-cultured fibroblasts were a component in some conditions to generate factors produced by resident stroma. We used a single-cell antibody-based hashing strategy to multiplex samples from different stimulatory conditions in one sequencing run. This macrophage transcriptomic data reveals distinct macrophage activation states and polarizations shaped by different tissue-related inflammatory conditions at single-cell resolution. We further performed an unbiased integration between tissue-level macrophages and this stimulated human blood-derived macrophages, which pinpoint an IFN-&#947; and TNF-&#945; synergistically driven inflammatory macrophage phenotype expanded in severe COVID-19 lungs and other inflamed disease tissues.

  Study phs002780

• DNA and RNA sequencing of single human haploid germ cells

  Our goal was to look at allele-specific gene expression in single spermatids from two human donors. We first genotyped and phased each donor using a combination of linked-read sequencing (one sample per donor, 10X Chromium), and single haploid whole genome sequencing (53 spermatids for the first donor, and 19 for the second).&nbsp;We then sequenced mRNA from single spermatids (302 from the first donor, and 164 from the second), using the Smart-Seq2 protocol. We used these gene expression data, in combination with the haplotype data, to look for gene products that exhibit allele-specific bias reflecting the haploid genotype of the cell.&nbsp;We find a large class of human genes that show such allele-specific bias in spermatids, indicating that these gene products are not fully shared across the cytoplasmic bridges that connect spermatids. We term these genes &#8220;genoinformative markers&#8221; (GIMs).

  Study phs002279

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): REasons for Geographic and Racial Differences in Stroke (REGARDS)

  Cohort DescriptionThe REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort is one of the nation&#39;s largest, most comprehensive population-based cohorts, and it uses innovative home- and telephone-based data collection. REGARDS centrally recruited and initially examined 30,239 Black and White men and women aged &#8805;45 years in 2003-7 to understand why Southerners and Black Americans have a higher incidence of stroke and related diseases that affect brain health.Data Being Submitted Wave 1 questionnaire data includes 397 variables for 8109 REGARDS participants in C4R. Wave 2 questionnaire data includes 448 variables for 6421 REGARDS participants in C4R. Dried Blood Spot/Serosurvey data includes 7 variables for 4058 REGARDS participants in C4R. Derived data includes 43 variables for 8606 REGARDS participants in C4R. Phenotype data includes 113 variables for 7880 REGARDS participants in C4R.

  Study phs002919

• The Genetic Evolution of Acral Melanoma

  Acral melanoma is a rare melanoma subtype arising on the sole, palm, or nail apparatus. We performed whole-exome sequencing (WES) for a cohort of 35 acral melanoma patients. For each patient, we sequenced multiple tumor areas representing different tumor stages, including the in situ and invasive portions of the primary tumor and available regional or distant metastases. Normal areas were included for all except one patient. We identified distinct evolutional trajectory compared to melanomas arising on the sun-exposed skin. Whole-genome sequencing and targeted sequencing were additionally performed for a subset of the samples. Particularly, in acral melanomas, complex genomic aberrations, characterized by clustered copy number transitions and focal amplifications, and telomerase reverse transcriptase (TERT) activating alterations occur very early during evolution, while MAP-kinase pathway mutations, such as BRAF V600E and NRAS hotspot mutations, can occur late and often result in striking intra-tumor heterogeneity.

  Study phs003451

• Origin of second malignancies in children

  Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary AML. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least in one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.

  Study EGAS50000000167

• Single-cell RNA sequencing of 16 NPM1 mutated AML patients

  NPM1 mutated AML is the largest class in WHO classification, however several subtypes within NPM1 were already reported. Here, we sequence 16 NPM1 mutated AML samples with single-cell RNA-sequencing and multi-color flow cytometry from three major NPM1 subtypes we previously identified, totaling more than half a million cells. We show that the differences among three NPM1 subtypes are mainly driven by cell composition, and these differences are also reflected at cell surface protein level. With the re-analysis of CITE-seq data from another cohort and single cell variant calling on our data, we also report two distinct stem cell phenotypes: one with leukemic (CD34dimCD38-CD45RA+) and another with pre-leukemic (CD34+CD38-CD45RA-) origin. We believe that our data and findings provide novel insights regarding the etiology of NPM1 mutated AML.

  Study EGAS50000000332

• The Formation and Propagation of Human Robertsonian Chromosomes

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

  Study phs003920

• A benchmark of DNA methylation deconvolution methods for tumoral fraction estimation using DecoNFlow

  In cancer patients, circulating cell-free DNA (cfDNA) originates from both healthy and cancer cells, and the proportion of tumor-derived cfDNA serves as a surrogate marker of tumor burden. Tumoral cfDNA can be identified using patient-specific mutations or more general tumor-specific DNA methylation patterns that are preserved in cfDNA, enabling non-invasive cancer detection and monitoring. Accurately estimating tumor fractions remains challenging due to the heterogeneous mixture of cfDNA sources in body fluids. Computational DNA methylation deconvolution methods can address this by estimating tumoral fraction with or without reference methylomes. Here, we benchmarked 10 reference-based and 2 reference-free DNAm deconvolution tools and provide the data generated for this benchmarking, consisting of 10 neuroblastoma cell lines and one healthy cfDNA sample (pooled from 15 healthy cfDNA samples), profiled using cfRRBS.

  Study EGAS50000001529

• An ancient DNA perspective on the Russian Conquest of Yakutia

  Yakut communities from northeastern Siberia inhabit some of the coldest environments on Earth preserving an extraordinary archaeological record. Their history was profoundly reshaped by the Russian conquest, which introduced cereals, pathogens and Christianity from 1632 CE. However, the biological impact of these transformations remains unknown. Here, we generated extensive ancient DNA data to elucidate contemporary changes in Yakut genomic diversity and oral microbiomes. We found Yakut origins tracing back to local populations that admixed with trans-Baikal groups migrating as the Great Mongol Empire spread. Despite the Russian conquest, the Yakut gene pool and oral microbiomes appeared largely stable, though smallpox strains distinct from those documented in Europe by ~1650 CE circulated. Marital practices generally maintained low consanguinity, with the exception of one female bearing the latest markers of traditional shamanism, who was the daughter of second-degree relatives.

  Study EGAS50000001329

• Whole-genome sequencing in 14 cases and whole-exome sequencing in 90 cases of Chinese ESCC

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 14 ESCC cases and whole-exome sequencing in 90 cases.

  Study EGAS00001001487

• Evolutionary analysis of pancreatic cancer and coexistent precursor lesions using whole exome sequencing data

  Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. Further, the evolution of these lesions contextualizes the dynamics of advanced stage disease. We analyzed the somatic variants of co-existing pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to a pancreatic cancer. We also found that this multi-step progression generally spans many years. Our data suggest that independent, high-grade pancreatic lesions observed in a histologic cross section often represent a single neoplasm that can spread and colonize the ductal system, accumulating spatial and genetic divergence over time.

  Study EGAS00001002778

• single nuclei RNASeq of 5 regions of the human prenatal brain

  Data generated through single nuclei RNA sequencing on 5 regions of the brain (frontal cortex, ganglionic eminence, hippocampus, thalamus and cerebellum) from 3 fetuses (two of 14 and one of 15 post-conception weeks, all female). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) with ethical approval. snRNA-seq libraries were prepared from ∼10,000 nuclei from each sample using Chromium Single Cell 3ʹ (v3) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 865 million (median = 1.01 billion) read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Biological Psychiatry 2022, https://doi.org/10.1016/j.biopsych.2022.06.033.

  Study EGAS00001006537

• Transcriptome Changes in ASD (NRXN1α+/-) iPSC-derived neurons

  NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons Quantitative RNA sequencing was performed by BGI using 50bp single-end strategy with BGI-SEQ500 sequencing device on iPSC-derived cortical neurons from 6 control lines; (2VC1, 3VCX1, 3VC2, 4C3, 4CX1, NCRM-1) of 4 healthy donors, and 4 NRXN1α+/- lines; (ND1C1, ND2C11, ND2CX1, ND4-1C2) from 3 ASD patients.

  Study EGAS00001005536

• Genome-wide cell-free DNA biological patterns in patients with cancer

  The structure of cell-free DNA (cfDNA) is altered in the blood of cancer patients. From whole genome sequencing we retrieved the cfDNA fragment-end composition using a new software (FrEIA), as well as the cfDNA size and tumor fraction in three independent cohorts (n=925 cancer from &gt;10 types and 321 control samples). At 95% specificity, we detect 72% of cancer samples using at least one cfDNA measure, including 64% of early-stage cancer (n=220). cfDNA detection correlates with a shorter overall (p=0.018) and recurrence-free (p=0.006) survival in patients with resectable esophageal adenocarcinoma. Integrating cfDNA measures with machine learning in an independent test set (n=396 cancer, 90 controls) achieve a detection accuracy of 82% and AUROC of 96%. In conclusion, harnessing the biological features of cfDNA can improve at no-extra cost the diagnostic performance of liquid biopsies.

  Study EGAS00001007400

• RNA sequencing in primary inflammatory (TPP) macrophages following deletion of a disease-associated gene desert at chr21q22, disruption of ETS2, or treatment of ETS2-edited macrophages with a HIF1α stabiliser.

  GWAS studies in five different inflammatory diseases have identified a strong genetic association at a gene desert at the chr21q22 locus. We have shown that this locus contains a monocyte/macrophage-specific enhancer that regulates ETS2 - a gene whose role in primary human monocytes/macrophages is incompletely understood. We therefore used a CRISPR-Cas9-based approach to delete the enhancer region or to disrupt ETS2, and performed RNA-sequencing to examine the transcriptional consequences. One effect of ETS2 disruption was upregulation of genes involved in aerobic respiration and oxidative phosphorylation. We therefore treated ETS2-edited inflammatory macrophages with roxadustat, a HIF1α stabiliser that can promote glycolysis via HIF1α-mediated metabolic reprogramming, and performed RNA-sequencing to determine whether this drug might rescue the transcriptional effects of ETS2 disruption.

  Study EGAS00001007553

• The Collaborative Study on the Genetics of Alcoholism (COGA)

  COGA 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 for 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. As part of COGA, a set of informative families was selected to have Genome-Wide Association data obtained within families. Genotyping was performed using the Illumina Human OmniExpress array 12.VI to genotype 2,282 subjects selected from 118 densely affected families. Genotyping was performed at the Genome Technology Access Center at Washington University School of Medicine in St. Louis. In addition, we also included genotypes for subjects (n=275 subjects) from these 118 families who were genotyped in a previous case-control GWAS using the Illumina 1M array. For quality control purposes, 51 of the 275 subjects were genotyped again on the Illumina Human OmniExpress array at the Washington University School of Medicine core facility.In addition, exome sequencing data on a subset of individuals with GWAS were added in version 2 (v2). For v2, a subset had 30X Whole Genome Sequencing (WGS) as part of the NIDA Sequencing Initiative. The subset contained two distinct sets: Sibling pairs where one sibling had at least two dependence diagnoses in the set (alcohol, cannabis, cocaine, and opioid), and the other had none, and non-related Case-Control pairs matched for age and ethnicity where the cases had alcohol and at least 2 other dependence diagnoses and controls had none. After sequencing, some sibling pairs are re-classified as half siblings. Three VCF files (small variants, structural variants, and copy number variations) are provided. Additional substance use variables are made available in v2. We note that the full sample data are deposited in four dbGaP submissions and the sequenced samples are split across all four: CIDR: Collaborative Study on the Genetics of Alcoholism Case Control Study [phs000125]. GWAS data on cases (primarily probands) and controls drawn from the families. Families with highest density of alcohol dependence and/or extreme event-related oscillation data [phs000763]. GWAS data on 119 extended families of European descent are available here, along with extensive documentation. Study on the Genetics of Alcoholism (COGA): African American Family GWAS [phs000976]. GWAS data on all available COGA families of African descent are available. COGA: Smokescreen GWAS [phs001208]. GWAS data on all remaining COGA DNA samples, primarily of other racial background, were genotyped on the Smoke Screen array. A listing of all sequenced pairs is provided in the documentation to facilitate the merging of these samples.

  Study phs000763

• Metagenomics-Guided Pathogen Discovery in Travelers' Diarrhea

  Traveler&#39;s diarrhea (TD) is caused by enterotoxigenic Escherichia coli (ETEC), other pathogenic gram-negative pathogens, norovirus and some parasites. Nevertheless, standard diagnostic methods fail to identify pathogens in more than 30% of TD patients, so it is predicted that new pathogens or groups of pathogens may be causative agents of disease. A comprehensive metagenomic study of the fecal microbiomes from 23 TD patients and seven healthy travelers was performed, all of which tested negative for the known etiologic agents of TD in standard tests. Metagenomic reads were assembled and the resulting contigs were subjected to semi-manual binning to assemble independent genomes from metagenomic pools. Taxonomic and functional annotations were conducted to assist identification of putative pathogens. We extracted 560 draft genomes, 320 of which were complete enough to be enough characterized as cellular genomes and 160 of which were bacteriophage genomes. We made predictions of the etiology of disease in individual subjects based on the properties and features of the recovered cellular genomes. Three subtypes of samples were observed. First were four patients with low diversity metagenomes that were predominated by one or more pathogenic E. coli strains. Annotation allowed prediction of pathogenic type in most cases. Second, five patients were co-infected with E. coli and other members of the Enterobacteriaceae, including antibiotic resistant Enterobacter, Klebsiella, and Citrobacter. Finally, several samples contained genomes that represented dark matter. In one of these samples we identified a TM7 genome that phylogenetically clustered with a strain isolated from wastewater and carries genes encoding potential virulence factors. We also observed a very high proportion of bacteriophage reads in some samples. The relative abundance of phage was significantly higher in healthy travelers when compared to TD patients. Our results highlight that assembly-based analysis revealed that diarrhea is often polymicrobial and includes members of the Enterobacteriaceae not normally associated with TD and have implicated a new member of the TM7 phylum as a potential player in diarrheal disease.

  Study phs001352

• NHLBI GO-ESP: Family Studies (Mendelian Lipid Disorders)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. In this study, we seek to identify the genetic cause of two monogenic lipid disorders-severe hypercholesterolemia and familial hypoalphalipoproteinemia. Monogenic severe hypercholesterolemia is clinically characterized by elevated total and low-density lipoprotein (LDL) cholesterol levels in plasma. Elevated LDL-cholesterol levels lead to excessive deposition of cholesterol in arterial walls, which eventually results in accelerated atherosclerosis and premature cardiovascular disease (CVD). Monogenic hypercholesterolemia has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. To date, mutations in the LDL receptor (LDLR) ligand-binding domains of APOB and PCSK9 have been shown to cause hypercholesterolemia. While mutations in these genes can explain a large percentage of clinically diagnosed patients, the underlying molecular determinant in a substantial fraction of patients remains unknown. Familial hypoalphalipoproteinemia (low HDL-C) is defined by an HDL-C below the age- and sex- specific 10th percentile. ABCA1, LCAT, and APOA1 are known to cause familial hypoalphalipoproteinemia. We hypothesize that: (1) additional novel genes responsible for Mendelian forms of low HDL-C exist; and (2) the causal gene and mutation(s) in each family may be discovered with exome analysis of just a few affected individuals in each pedigree.

  Study phs000587

• UK10K NEURO GURLING

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of DNA from multiply affected schizophrenia families. The families have been diagnosed using the SADS-L clinical instrument which gives diagnoses at the probable level of the research diagnostic criteria (RDC). In addition all diagnoses are available using DSMIIIR criteria. These criteria are widely accepted as being valid and reliable for the diagnosis of schizophrenia. All families have been collected to ensure that they are uni-lineal for transmission of schizophrenia, i.e. they have only one affected parent with schizophrenia, or a relative of only one transmitting or obligate carrier parent with schizophrenia. Families with bi-lineal transmission of schizophrenia (i.e. with both parents being affected) were not sampled for this study. All families have multiple cases of schizophrenia and related disorders. The families have been selected to ensure there are no cases of bipolar disorder within them and that they do not contain bipolar disorder in any relatives on either side of the family.For further information on this cohort please contact Hugh Gurling (h.gurling@ucl.ac.uk).

  Study EGAS00001000225

• 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

• Genetic Epidemiology of Refractive Error in the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) Study

  KORA ("Kooperative Gesundheitsforschung in der Region Augsburg" which translates as "Cooperative Health Research in the Region of Augsburg") is a population based study of adults randomly selected from 430,000 inhabitants living in Augsburg and 16 surrounding counties in Germany. The collection was done in 4 separate groups from 1984-2001 (S1-S4). One of the KORA groups, S3/F3, will be utilized for our GWAS because it is the only group with refractive error (RE) measurements. Consequent to informed consent, each of the surveys sampled subjects from ten strata according to age (range 25-74 years) and sex (equal ratio) with a minimum stratum size of &gt; 400 subjects. In the KORA S3 study 4,856 subjects were studied between 1994 and 1995, and 3,006 individuals from S3 returned for follow up between 2003 and 2005 (S3/F3). For this refractive error study, we are including 1,981 subjects from S3/F3 (mean age 55.7, range 35-84). For each subject, eyeglass prescriptions were measured in addition to an evaluation by the Nikon Retinomax. Subjects with predisposing medical conditions, i.e., connective tissue disorders, and ocular conditions i.e., cataract and corneal opacities, that might predispose them to refractive error will not be included for genotyping. Whole genome association genotyping will be performed to determine common alleles that contribute to the variation of the quantitative trait of refractive error.

  Study phs000303

• Longitudinal single-cell transcriptomic study in patient-derived xenografts of pediatric T-ALL

  In this study, we conducted single cell full length total RNA sequencing (VASA-seq) on 13 matched pediatric T-ALL PDX samples at initial diagnosis and relapse, along with 5 non-relapsing PDX samples collected at initial diagnosis. We identified a subpopulation of T-ALL cells with stem-like cell features that expands substantially at relapse indicating resistance to first-line therapy. Chemotherapy resistance was further validated through functional testing: Two samples were subjected to in-vitro drug testing, treated with Cytarabine for three days, followed by single-cell transcriptomic analysis using 10x Genomics. Additionally, in-vivo drug testing was conducted on one sample, involving re-engraftment into mice and treatment with a combination of Vincristine, Doxorubicin, and Dexamethasone. Single-cell transcriptomic analysis using 10x Genomics was performed after 0, 15 and 30 days of treatment.

  Dataset EGAD50000000831

• DAC Dr. PORTEU – Gustave Roussy

  Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways Data Access Committee Members (Name, Email, Job Title): Principal Investigator PORTEU Françoise (FRANCOISE.PORTEU@gustaveroussy.fr) Head of Bioinformatics platform DELOGER Marc (Marc.DELOGER@gustaveroussy.fr) Data Protection Officer BECHET Clara (Clara.BECHET@gustaveroussy.fr)

  Dac EGAC50000000252

• Genetic Components of Knee Osteoarthritis (GeCKO) Study: The Osteoarthritis Initiative

  The Osteoarthritis Initiative (OAI) is a publicly and privately funded prospective longitudinal cohort with a primary objective of identifying risk factors for incidence and progression of tibiofemoral knee OA. The OAI utilized a focused population-based recruitment to enroll 4,674 men and women between the ages of 45-79 years who either had radiographic symptomatic knee OA or who were without radiographic symptomatic OA in both knees but were considered high risk for OA because they had two or more known risk factors for knee OA. Subjects were recruited into the baseline phase of the OAI at multiple sites throughout the US between 2004 and 2006. All subjects were invited back for follow-up examinations to assess incidence or progression of OA annually, for up to 5 years. Phenotype data from the baseline and follow-up examinations are available for public access from the Osteoarthritis Initiative (OAI) database at http://www.oai.ucsf.edu/. The Genetic Components of Knee Osteoarthritis (GeCKO) Study was initiated in 2009 as a genetic ancillary study to perform a genome-wide association study to identify genetic variants associated with radiographic osteoarthritis. This study included 4,482 individuals participating in the parent OAI study. Following sample cleaning (e.g., removal of duplicates, sex mismatches, poor sample quality, etc.), the final sample set included 4,129 individuals.

  Study phs000955

• Jackson Heart Study (JHS-BioLINCC)

  Accessing Data: Please refer to &#8220;Authorized Access&#8221; below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Related Studies: Other Jackson Heart Study data available include: Imaging studies (JHS-Imaging), Genetics and genomics (The Jackson Heart Study, phs000286.v7.p2), and Collaborative Cohort of Cohorts for COVID-19 Research (C4R-JHS, phs002907.v1.p1): Jackson Heart Study (phs002907.v1.p1).Available Data: Data available for request include Jackson Heart Study visit 1-3 examination cycles, collated annual follow-up communication data through 2016, and follow-up for mortality, heart disease, and stroke events through 2014.Objectives: The objectives of the Jackson Heart Study are to: 1) investigate the associations of biological, psychosocial, and behavioral factors with the incidence atherosclerotic events and health outcomes in an African American cohort; and 2) increase access to and the participation of African American populations and scientists in biomedical research and professions.Background: It has long been recognized that African Americans share a disproportionate burden of deleterious health outcomes including diabetes, hypertension, kidney disease and early onset of cardiovascular disease. The Jackson Heart Study was initiated in 2000 to explore potential mechanisms and mediators of health outcomes in a large African American cohort. In addition, the JHS conducts a variety of community education and outreach activities to promote healthy lifestyles to reduce disease risk burden and student training programs to promote and support public health research.Participants: African American men and women, age 35-84 at entry. Of the 5306 cohort members enrolled in the study, the data repository contains data from 3,883 that provided informed consent to share their data with investigators not affiliated with the study.Design: Participants were enrolled in the study from 2000-2004 from urban and rural areas of three counties (Hinds, Madison and Rankin) in the Jackson, MS metropolitan statistical area. Participants were enrolled from each of 4 recruitment pools: a random sample component (17%), volunteer component (30%), currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study (31%), and secondary family members (22%). Recruitment was limited to non-institutionalized adult African Americans age 35-84 years, except in the family cohort where those age &#8805;21 years were eligible. The final cohort of 5,306 participants includes 6.59% of all African American residents aged 35-84 (N=76,426, US Census 2000). Data collection at the baseline exam included a medical history, physical examination, blood/urine analytes and interview questions on areas such as: physical activity; stress, coping and spirituality; racism and discrimination; socioeconomic status; and health care access.The current release of the Jackson Heart Study includes data collected at baseline, exam 2 (2005-2008), and exam 3 (2009-2013). Annual follow-up and surveillance of clinical cardiovascular events is ongoing.

  Study phs003740

• A Large Data Resource of Genomic Copy Number Variation across Neurodevelopmental Disorders

  This study presents the first genome-wide copy number variation (CNV) analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD). A total of 2,691 subjects diagnosed with a neurodevelopmental disorder (NDD), and a total of 1,769 unaffected family members from Ontario, Canada were assayed using the Affymetrix CytoScan HD array. We identified rare CNVs, (&lt; 0.1% frequency in 10,851 population control samples), and found clinically relevant CNVs in 10.5% of total subjects. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244, NRON, and PTCHD1-AS. We demonstrated that identical CNVs or genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants and clinical interpretations.CNV data from this study are available through dbVar at https://www.ncbi.nlm.nih.gov/dbvar/studies/nstd173/.

  Study phs001881

• Genetic Predictors of Ibrutinib-Related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia

  The goal of this study was to identify genetic polymorphisms associated with ibrutinib-related cardiovascular side effects (CVSEs). This is an observational non-interventional pharmacogenomic study of 50 patients with newly diagnosed or relapsed refractory chronic lymphocytic leukemia (NDCLL or RRCLL) receiving ibrutinib 420 mg for at least six months. The ibrutinib-related CVSEs included atrial fibrillation and hypertension, which occurred in 20% of patients. DNA obtained from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA5, NPPA, and SCN5A using a customized next generation sequencing panel. It was found that GATA4 rs804280 AA (P =.043), KCNQ1 rs163182 GG (P =.036) and KCNQ1 rs2237895 AA (P =.023) were associated with the ibrutinib-related CVSEs. Patients with a high-risk score had at least two of the three significant risk genotypes identified in univariate analysis for GATA4 rs804280 A&gt;C, KCNQ1 rs162182 G&gt;C and KCNQ1 rs2237895 A&gt;C, and patients with a low-risk score had either one or none of these genotypes. In multivariate analysis, 18 patients with at least two of the three high-risk genotypes had an 11.5-fold higher odds of CVSEs (P =.019; 1.79-119.73 at 95% CI).

  Study phs003370

• The Prediction and Prevention of Preeclampsia

  The Prediction and Prevention of Preeclampsia (PREDO) is a prospective birth cohort study of Finnish women who were pregnant between 2005 and 2010 and their children. The PREDO study cohort was set up to identify novel risk factors and biomarkers in pregnant women associated with the development of preeclampsia and intrauterine growth restriction (IUGR). Two groups of pregnant women were enrolled during the first trimester of their pregnancy: first, pregnant women with a known clinical risk factor status for preeclampsia and IUGR (N=1079; 969 of these women had at least one and 110 had none of the known risk factors for preeclampsia and IUGR), and second, pregnant women who volunteered to participate regardless of their risk factor status for preeclampsia and IUGR (N=3698). Both samples were monitored during pregnancy with four clinical visits and bi-weekly self-reports. The post-delivery follow-up has taken place at approximately 2 weeks, 6 months, and 3.5 years after the delivery. The most recent follow-up started in 2016 and is ongoing. In the high-risk sample, cord blood samples were collected and genome-wide genotyping has been conducted with Illumina OmniExpressExome 1.2 and genome-wide methylation status has been analysed with Illumina 450k HM array.

  Study EGAS00001001898

• DNA methylation-based classification of sinonasal tumors [Proteomics data]

  This dataset includes raw label-free mass spectrometry proteomics data of different sinonasal tumor entities as well as normal sinonasal tissue. 72 samples were processed on a Q Exactive HF-X instrument coupled to an easy nanoLC 1200 system using one microgram of peptides and an 110 minutes gradient.

  Dataset EGAD00010002381

• Dataset for "HPV integration induces gene fusions" (RNA)

  RNA-seq data for "HPV integration induces gene fusions" We performed RNA-seq analysis of five HPV+ head and neck cancer samples using Illumina short reads. Sequenced are submitted in bam format. We also sequenced one samples with pacBio long reads, and the reads are submitted in fastq format.

  Dataset EGAD50000001303

• Whole genome sequencing data of pediatric hypodiploid B cell acute lymphoblastic leukemia

  The dataset includes FASTQ and BAM files from diagnostic and matched remission (control) bone marrow samples of one hypodiploid ALL patient (ALLT-351). Sequencing library was made using NEB Next® Ultra™ DNA Library Prep Kit. Both diagnostic (60x) and remission (30x) samples were sequenced using HiSeq X.

  Dataset EGAD50000001856

• PacBio Revio WGS on 10 carriers of ring and marker chromosomes

  Bam files containing PacBio HiFi reads from carriers of ring and marker chromosomes. The reads where genereated using the PacBio Revio platform. Each individual was sequenced to roughly 30X coverage on one flow cell per individual. The chromosome of interest is indicated in the file name.

  Dataset EGAD50000002111

• RNA-seq iNKT, T and C1R cells

  RNA-seq (Ribodepleted Directional -75 PE- Hiseq 4000) data of purified and expanded iNKt and T cells from normal donor, and RNA-seq (poly-A 100-PE Hiseq 2500) data from C1R cell line. Data set consist of 3 pairs of fastq files, one pair per sample

  Dataset EGAD00001004331

• Spatial transcriptomics of 1 untreated prostate cancer.

  Two sections of cryopreserved prostate cancer tissue from one untreated prostate cancer patient were profiled for spatial transcriptomics using the Visium Spatial library preparation protocol from 10x Genomics. The GRCh38 aligned sequencing reads from the two prostate cancer tissue sections are provided as BAM files.

  Dataset EGAD00001007921

• Demultiplexed FASTQs for each volunteer

  This submission consists of 15 volunteer FASTQs, split by chemistry: Chemistry v1.1: 7 FASTQ sets, one set for each volunteer (RA1-7) Chemistry v2: 16 FASTQ sets, two for each volunteer (RA8-15; FASTQ set 1: Gene Expression (GEX); FASTQ set 2: TCR enrichment (VDJ))

  Dataset EGAD00001007586

• What is metadata?

  What is metadata? Data represents units of information and metadata can be seen, simply put, as data about other data. For example, in a simple experiment in which a patient genome was sequenced, there are multiple and diverse fields of metadata: from the biological sex of the patient to the sequencing platform used. Another way to understand metadata, following our genomic experiment example, is going through the different layers of (meta)data: One of the basic units of information (data) would be the sequence of nucleotides (e.g. GCTGG and GCCGG). This DNA sequence can be contextualised within a chromosome by providing its locus (e.g. β-globin gene). This data, the locus, is about other data, the sequence of nucleotides, which would render it metadata. We can go one step further, and provide more context, by giving the associated phenotype of each of these sequences: GCTGG corresponds to a healthy individual, while GCCGG corresponds to a person with β-thalassaemia. Once again, this data is contextualising the data we have provided up to this point, which makes it metadata. With this simple example, what we are doing is adding layers of data that describe the ones below. Had we given the sequences alone, little would be possible from the researchers' point of view. But, now that the data has its accompanying metadata, a researcher could compare both sequences and their phenotypes to infer a possible cause of the disorder. Each layer of information broadens the possible applications of the data. Now that we know what metadata is, it is time to emphasise the importance of submitting good quality metadata. The quality of the metadata will determine whether the data is usable, discoverable, and interpretable by researchers and clinicians. One example that highlights the importance of good quality metadata is the description of biological sex of a patient: while the terms "female," "girl," or "woman" all represent the same concept, they are not harmonised. These different representations of a concept can create confusion and errors in data analysis. By applying standard definitions and terminologies to biological sex metadata, we can avoid misunderstandings and facilitate the integration of different datasets.  In order to comply with the FAIR principles and, more specifically, to allow for the (meta)data to be interoperable (i.e. used universally and unambiguously), we need to place some standards onto the (meta)data EGA  archives. These can be as simple as asserting that the given patient's biological sex is one of the correct terms (e.g. female or male); or as complex as multiple layers and combinations of validation steps with existing records. You can find further details on how EGA manages these standards on our metadata model page.

  Documentation submission/metadata/what-is-metadata

• Tumor gene expression profiles for the study "TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells"

  RNA was extracted from formalin-fixed and paraffin embedded tumors of a large cohort of bladder cancer patients before treatment with anti-PD-L1. RNA was sequenced using a capture based approach (exome capture, RNA access).

  Dataset EGAD00001003977

• AIDS Linked to the Intravenous Experience (ALIVE) Cohort

  The AIDS Linked to the Intravenous Experience (ALIVE) Study is a long-standing community based research effort that includes past and current injection drug users (IDUs). ALIVE has been ongoing since 1988 and is one of the longest-running community-based cohorts of IDUs in existence. The primary objectives when the study started were to characterize the incidence and natural history of HIV among injection drug users (IDUs). At each study visit, participants undergo a series of questionnaires that elicit information about substance use (including drugs used and route of administration) and a blood draw. A subsample of 1200 subjects was selected for genotyping for the NIDA Smokescreen effort who report heroin injection and have existing peripheral blood samples (isolated buffy coat). In addition to injected heroin, ALIVE subjects are assessed on lifetime and previous six months use of marijuana (76.3%), crack (55.5%), snorted cocaine (48.3%), injected cocaine (89.9%), injected speedball (87.0%), and smoking heroin (9.0%). The sample is 33.4% female, &#126;85% African-American and assessed through a mean maximum age of 49.9 years old. Importantly, subjects are not assessed to meet DSM criteria, but all subjects report having injected drugs. We provide demographic data (age at assessment, sex, self-reported race) and drug use data (lifetime &#34;use&#34; ever endorsed) for each drug class/route described above for each subject

  Study phs001494

• NHLBI TOPMed: Novel Risk Factors for the Development of Atrial Fibrillation in Women

  The Women's Genome Health Study (WGHS) is a prospective cohort comprised of over 25,000 initially healthy female health professionals enrolled in the Women's Health Study, which began in 1992-1994. All participants in WGHS provided baseline blood samples and extensive survey data. Women who reported atrial fibrillation during the course of the study were asked to report diagnoses of AF at baseline, 48 months, and then annually thereafter. Participants enrolled in the continued observational follow-up who reported an incident AF event on at least one yearly questionnaire were sent an additional questionnaire to confirm the episode and to collect additional information. They were also asked for permission to review their medical records, particularly available ECGs, rhythm strips, 24-hour ECGs, and information on cardiac structure and function. For all deceased participants who reported AF during the trial and extended follow-up period, family members were contacted to obtain consent and additional relevant information. An end-point committee of physicians reviewed medical records for reported events according to predefined criteria. An incident AF event was confirmed if there was ECG evidence of AF or if a medical report clearly indicated a personal history of AF. The earliest date in the medical records when documentation was believed to have occurred was set as the date of onset of AF.

  Study phs001040

• ApoA-1 and Atherosclerosis in Psoriasis

  Apolipoprotein A-1 is a protein localized to high-density lipoprotein that functions to remove cholesterol from tissues for transport back to the liver. Psoriasis is a systemic inflammatory disease associated with poor high-density lipoprotein function and accelerated non-calcified burden by coronary computed tomographic angiography. In this study, 310 psoriasis patients from The Psoriasis, Atherosclerosis, and Cardiometabolic Disease Initiative (PACI) were studied at baseline to determine if levels of circulating apolipoprotein A-1 predict early onset coronary artery disease in inflammatory conditions. Of the 310 participants, 124 were followed for four years to determine if apolipoprotein A-1 predicts non-calcified coronary burden over time. The primary outcome of this study was non-calcified coronary burden by coronary computed tomography angiography. To assess non-calcified coronary burden, participants underwent coronary computed tomography angiography using the same scanner (320-detector row Aquilion ONE ViSION, Toshiba, Japan). For ApoA-1 quantification, fasting blood draw was performed the same day as the coronary computed tomography angiography. The 400MHz proton Vantera Clinical Analyzer was used to quantify Plasma apolipoprotein A-1. The study determined that low levels of apolipoprotein A-1 are associated with increased coronary artery burden and that this relationship persists over time. The data are available through dbGaP and the dataset includes all variables reported in the manuscript.

  Study phs003231

• NHLBI TOPMed: Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

  During Visit One, the PUSH Study will perform echocardiography on 600 children and adolescent with patients with sickle cell disease (SCD) and 100 control children and adolescents at three Field Centers, namely Howard University, Children's National Medical Center and University of Michigan. Patients or their parents will be approached and asked to give informed consent. If they appear to have a difficult reading, reading of the consent will be offered. Patients or their parents not appearing to comprehend the consent will not be eligible. As a part of this visit, each participant or parent will sign informed consent, complete a Participant Contact Information Form, complete a Medical History Form, undergo physical examination with completion of a Physical Examination Form and have blood drawn. Each participant must have echocardiography performed with measurement of Tricuspid Regurgitant Jet Velocity (TRV). In addition, attempts will be made 1) to perform a six-minute walk test, 2) to collect information from a recent (within six months) Transcranial Doppler Study (TCD) or to perform TCD, and 3) to perform pulmonary function tests. Study personnel will review all forms for completeness and conduct phlebotomy. Blood will be shipped to the Central Lab. Results of all procedures and tests will be transmitted to the Data Manager at Howard University. Sequencing was only done on sickle cell participants.

  Study phs001682

• 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

• Blueprint Data Access Committee.

  Access to the sequence and alignment and genotype level data produced by the Blueprint Consortium is controlled by the Blueprint Data Access Committee (DAC). Access to data will be granted to qualified investigators for appropriate use. Please email blueprint-dac@ebi.ac.uk to request the Data Access Application and Data Access Agreement.

  Dac EGAC00001000135

• Weighing Risks and Benefits of Laparoscopic Anti-Reflux Surgery in Patients With Idiopathic Pulmonary Fibrosis (WRAP-IPF-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: To determine if the reduction of abnormal gastro-esophageal reflux (GER) with laparoscopic anti-reflux surgery will slow the progression of idiopathic pulmonary fibrosis (IPF) as measured by forced vital capacity (FVC).Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause and increasing prevalence in the United States. Aside from lung transplantation, which approximately only 1% of participants will receive, there is no FDA-approved therapy. Abnormal acid gastro-esophageal reflux (GER) has been well described in participants with IPF and is thought to play a role in the progression of the disease. The several retrospective cohort studies that have assessed the association of anti-acid therapies for GER with clinical outcomes in IPF have had inconsistent results.Participants: A total of 58 participants were enrolled.Design: The WRAP-IPF trial was a multicenter, unblinded randomized clinical trial with participants randomized to either laparoscopic anti-reflux surgery or no surgery. Participants in the no-surgery group had the option of receiving laparoscopic anti-reflux surgery from 24 weeks after randomization if their clinician deemed it medically necessary. Medications for acid GER were allowed in both groups if the clinician felt it was necessary.Participants were followed up from time of randomization to 52 weeks. All participants had study visits at baseline, 12, 24, 36, and 48 weeks, during which spirometry, 6-min walk testing, and participant-related outcome assessments were done. Participants in the surgery group had clinical visits for preoperative evaluation, laparoscopic anti-reflux surgery, and postoperative management as clinically indicated. Surgery participants additionally underwent repeat 24-hour pH testing at 24 weeks to assess the efficacy of the surgery. All participants were contacted by telephone for safety assessments at weeks 4, 8, 16, 20, 28, 32, 40, 44, and 52. All participants completed an exploratory questionnaire on reflux symptoms at baseline and 48 weeks. The primary endpoint was change in FVC from randomization (baseline) to 48 weeks. Secondary endpoints included acute exacerbation, non-elective hospitalization (both all-cause and respiratory-related), death, change in cough severity, change in dyspnea severity, change in health-related quality of life, change in 6-min walk distance, and time to selected event-driven composite endpoints of disease progression. Conclusions: In participants with IPF and abnormal acid GER, laparoscopic anti-reflux surgery is safe and well tolerated but did not significantly slow the rate of FVC decline. Further research is needed, particularly with a larger study in order to achieve sufficient statistical power, regarding the possible benefits of anti-reflux surgery in this population.Raghu G, Pellegrini CA, Yow E, et al. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): a multicentre, randomised, controlled phase 2 trial. Reference: Raghu, et al., 2018; PMID: 30100404.

  Study phs003968

• Versatile workflow for cell-type resolved transcriptional and epigenetic profiles from cryopreserved human lung

  The complexity of the lung microenvironment and changes in cellular composition during disease progression make it exceptionally hard to understand molecular mechanisms leading to the development of chronic lung diseases. Although recent advances in cell-type resolved and single-cell sequencing approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a novel, versatile workflow that allows long-term storage of human lung tissue with high cell viability, permits thorough sample quality check before cell isolation, and is compatible with sequencing-based profiling, including single-cell approaches. We demonstrate that cryopreservation is suitable for the isolation of multiple cell types from human lung and is applicable to both healthy and diseased tissue, including COPD and tumour samples. Basal cells isolated from cryopreserved airways retain the ability to differentiate, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that genome-wide gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for -omics profiling of human lung cells. In addition, we obtained high-quality single-cell RNA sequencing data of cells isolated from the cryopreserved human lung, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our cryopreservation workflow is well-suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to human tissue.

  Study EGAS00001004477

• PCA Atlas Chromium scRNA-seq and demultiplexing support (FASTQs, BAMs, capture-level VCFs and mapping tables)

  This dataset contains Chromium single-cell RNA-seq data and demultiplexing support for the PCA Atlas study EGAS00001008332. Included data objects: - 16 Chromium scRNA-seq FASTQ runs (EGAR accessions) for captures PCa1–PCa16. - 16 aligned BAM analyses (one Cell Ranger possorted_genome_bam.bam per capture). - 16 capture-level genotype VCF analyses derived from the Axiom UK Biobank array, used as demultiplexing panels. - demux_map.csv (EGAZ00001945520): donor–capture–sample mapping for genotype-based demultiplexing. - chromium.csv (EGAZ00001945537): run-level mapping linking captures, EGA samples, runs (EGAR), experiments (EGAX) and BAM analyses. Together these objects provide a complete view of the Chromium scRNA-seq data and the genotype-based demultiplexing support needed to reproduce donor assignment and downstream analyses.See also https://zenodo.org/records/17372603

  Dataset EGAD00001015795

• Virginia PrIMeD Study

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

  Study phs003609

• National Institute of Arthritis and Musculoskeletal and Skin Diseases and Istanbul Faculty of Medicine Genome-wide Association Study of Behçet's Disease (Turkish)

  IntroductionBeh&#231;et&#39;s disease (BD) is a genetically complex multisystem disease of unknown etiology, characterized by recurrent inflammatory attacks affecting orogenital mucosa, eyes, skin, joints, blood vessels, and less frequently, the central nervous system and gastrointestinal tract. Family studies suggest a genetically complex contribution to BD. With the exception of HLA-B51, which explains less than 20% of the genetic risk, the identities of alleles that are responsible for the complex inheritance of this disease have remained unclear. AimTo identify genes that contribute to BD susceptibility. MethodsA genome-wide association study was undertaken with 311,459 informative and high quality SNPs in a collection of 1215 BD patients and 1278 healthy controls from Turkey using a beadchip microarray assay (Infinium SNP genotype assay, Illumina). HLA-B types were determined with a reverse sequence-specific oligonucleotide method (One Lambda). Regions with evidence for association were fine-mapped using Sequenom iPLEX gold assays. Disease-associated SNPs were genotyped in additional ethnically matched case/control collections from diverse genetic backgrounds, including a total of 2430 cases and 2660 controls, using TaqMan SNP genotype assays. Association data were combined in a meta-analysis of all the collections. ResultsWe confirmed the known association with HLA-B51 and found evidence for a second, independent susceptibility locus in the Class I region of the MHC. In addition, we identified one SNP with genome-wide evidence for disease association (P &lt; 5.0 x 10-8) within the gene encoding the immunoregulatory cytokine, interleukin-10 (IL10). A meta-analysis of the data from all the collections established associations with the IL10 variant (rs1518111, P = 3.54 x 10-18, odds ratio 1.45 with 95% confidence interval 1.34 to 1.58) and with a variant located between the interleukin-23 receptor (IL23R) and interleukin 12 receptor &#946;2 (IL12RB2) genes (rs924080, P = 6.69 x 10-9, odds ratio 1.28 with 95% confidence interval 1.18 to 1.39). The disease-associated IL10 variant was associated with diminished mRNA expression and low protein production by cells obtained from healthy blood donors. ConclusionsThese data suggest that genetically encoded low production of IL-10 increases risk of BD and suggest novel interventional targets in the IL-10 and IL-23 pathways. Note: The submitted data are the genotypes of the 311,459 SNPs in 1215 cases and 1278 controls.

  Study phs000272

• Tools

  EGA Tools This page provides details of the applications available at the EGA. Submission Tool Description EgaCryptor Encrypt and create md5sum values. Crypt4gh Encrypt, decrypt or re-encrypt files. INBOX Upload your files once encrypted. FTP Upload your files once encrypted. Submitter Portal Submit and manage your submission metadata online (SEQUENCING AND PHENOTYPE ONLY) Submitter Portal API Submit and manage your submission metadata programmatically. Webin Submit and manage your submission metadata online (array data) Webin API Submit metadata using XML files. Aimed to array-based submissions. Star2xml Format conversion tool to transform tabular formats (e.g. spreadsheets) into EGA's XMLs. Used for large programmatic submissions. Data Access Tool Description DAC Portal Manage and control data access request. Download Tool Description PyEGA3 Download and decrypt datasets requested through your EGA web account. Live Outbox Download and decrypt datasets requested through your EGA web account. Fuse Client A quick and convenient way to browse through EGA files without the need for complete downloads. EGA QuickView A quick and convenient way to browse through EGA files without the need for complete downloads.

  Documentation tools

• TCGA WGS Variants Across 18 Cancer Types

  Even though whole genome sequence (WGS) data has been generated and published in many studies, much of this information is not yet processed for use in down-stream analysis. This study's aim is to provide 1342 WGS normal-tumor paired single nucleotide variations (SNP) over 18 different cancer types provided by The Cancer Genome Atlas (TCGA) project. Individual level data for TCGA can be accessed by requesting access for phs000178. This data includes variations within self-reported white and African-American populations. Variations that exist within the tumor tissue but are absent in associated normal organ tissue (as compared to the human reference genome) are reported. Data published includes SNP and small insertions and deletions, which were generated through a pipeline including the VarScan2 variant calling software.

  Study phs003155

• Pulmonary atypical carcinoid multi-omic dataset on up to 42 tumours from same patient

  Pulmonary atypical carcinoid. DNA WES and RNA-Seq on 42 tumour samples collected at autopsy, 10x Chromium linked read whole genome sequencing on four tumours plus one normal sample, and targeted DNA sequencing on two clinical biopsies and one blood plasma sample. Note – RNA-Seq dataset features complex batch effect attributable to tissue processing artefacts, as described in "Complex patterns of genomic heterogeneity identified in 42 tumor samples and ctDNA of a pulmonary atypical carcinoid patient" - Robb et al., 2022 and detailed in Supplementary Table S3. Note – RNA-Seq dataset features complex batch effect attributable to tissue processing artefacts, as described in "Complex patterns of genomic heterogeneity identified in 42 tumor samples and ctDNA of a pulmonary atypical carcinoid patient" - Robb et al., 2022 and detailed in Supplementary Table S3.

  Dataset EGAD00001009296

• Ischemic Stroke Genetics Study (ISGS)

  The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors. These well characterized risk factors that contribute to the incidence of stroke include hypertension, cardiac disease, sickle cell disease, hyperhomocysteinemia, family history of stroke and smoking. ISGS aim is to perform a prospective genetic association study of ischemic stroke focusing on the hemostatic system. ISGS is a 5-center case-control study of first-ever ischemic stroke cases and concurrent controls individually matched for age, sex and recruitment site. This data includes that from subjects both banked in the NINDS repository with biologicals publicly available, and those whose samples are not banked/not available. Important links to apply for individual-level data Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Participant Protection Policy FAQ --> This study utilized the NINDS Repository Cerebrovascular/Stroke Study, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection for a first stage whole genome analysis.

  Study phs000102

• Resuscitation Outcomes Consortium (ROC) Prehospital Resuscitation on Helicopter Study (PROHS) (ROC-PROHS-BioLINCC)

  Accessing Data: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Objective: To observe if patients with severe traumatic injuries evacuated to level 1 trauma centers on air ambulances who received prehospital red blood cells and/or plasma had decreased in-hospital mortality compared to patients who received only crystalloids.Background: Injury is the leading cause of death in adults and children between the ages of 1 and 44 years. However, approximately 40% of in-hospital deaths among injured patients involve massive truncal hemorrhage that is considered potentially salvageable. Multiple retrospective military and civilian studies have reported that transfusion involving blood component ratios approaching whole blood are associated with significant decreases in 24-hour and 30-day mortality among injured patients. Furthermore, prehospital transfusion (PHT) studies from military and civilian hospitals have shown that prehospital transfusion of plasma and red blood cells (RBCs) is not only feasible, but associated with improved coagulation status on arrival. Prehospital resuscitation practices in the US differ significantly in approach, with most systems using crystalloids while a few offer RBCs or a combination of plasma and RBCs. No large multicenter civilian studies have evaluated the use of prehospital plasma and RBCs in severely injured patients compared to crystalloids.Participants: A total of 25,118 trauma patients were admitted during the 10 month enrollment period to the nine participating centers, of which 2341 arrived by helicopter, and 1058 met the highest risk criteria. Of the high risk sub-set, 585 arrived on helicopters with blood products available and 473 patients arrived via helicopters without blood available. One hundred forty two patients (24%) of those transported on helicopters with blood products available actually received PHT and 916 patients did not.Design: PROHS was a multicenter, prospective pragmatic, observational study of prehospital resuscitation approaches. There were no study guidelines dictating resuscitation practice (i.e., use of blood products or end of resuscitation). Of the 9 participating Level I trauma centers, 5 had helicopter systems with plasma and/or RBCs while the other 4 had helicopter systems that used only crystalloid resuscitation. All patients arriving to the participating center's trauma emergency department via helicopter directly from the scene were screened and had initial data collected. Of that group, all patients who met the highest risk category or received blood during transport were followed by direct observation during the initial resuscitation period and then indirectly through medical chart review until hospital discharge or 30 days after admission (whichever occurred first).The primary outcome was in-hospital mortality at 3 hours, 24 hours, and 30 days. Other outcome measures included length of hospital stay, number of ICU days, number of ventilator days, blood product usage, GOSE score at discharge, number of patients with complications, and number of patients who required hemostatic devices. Conclusions:Because of the unexpected imbalance in injury severity between systems with and without blood products on helicopters, all analyses were inconclusive. With few units transfused to each patient and small outcome differences between groups, large randomized studies will be required to detect significant survival differences in this important population.

  Study phs003826

• cfDNA sWGS BAM — Metastatic colorectal cancer

  Plasma cirDNA sWGS for metastatic colorectal adenocarcinoma at diagnosis prior to systemic therapy. Libraries DSP/SSP (per sample). Sequencing by IntegraGen (2022–2024). Alignment: GRCh38 with BWA-MEM; BAMs sorted/indexed; delivered as primary mapped reads only (filters/MAPQ in analysis metadata). Controlled access

  Dataset EGAD50000001879

• EFFORT occupationally exposed human stool metagenomes (148 samples)

  Metagenomes of stool samples from 54 pig farmers, 24 broiler farmers and 70 slaughter line workers. Note: Access to the data will only be granted for antibiotic resistance studies in accordance with the EFFORT consents issued by the participants.

  Dataset EGAD00001005444

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel&#39;s team at Children&#39;s Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Primary Prostate Tumor Tissue DNA Methylation Profiles

  The study cohort includes 525 Caucasian and African American prostate cancer (PCa) patients who underwent radical prostatectomy (RP) as primary therapy for clinically localized adenocarcinoma of the prostate. These patients were previously enrolled in one of two population-based studies: 1) men 40-64 years of age, diagnosed between January 1993 and December 1996; and, 2) men 35-74 years of age, diagnosed between January 2002 and December 2005. Gleason grade and sum, diagnostic PSA, and pathological tumor stage were obtained from the SEER cancer registry. Formalin-fixed paraffin-embedded prostate tumor tissue blocks were obtained from RP specimens and used to make hematoxalin and eosin stained slides, which were reviewed by pathologists to confirm the presence/location of adenocarcinoma. For each patient two 1-mm tumor tissue cores from the dominant lesion that were enriched with &#62;&#61;75% tumor cells were taken for DNA purification. The RecoverAll Total Nucleic Acid Isolation Kit (Ambion/Applied Biosciences, Austin, TX) was used to extract DNA, which was then quantified (PicoGreen), aliquoted onto 96-well plates and shipped to Illumina for DNA methylation profiling using the Infinium&#174; HumanMethylation450 BeadChip.

  Study phs001921

• Kids First: Whole Genome Sequencing of Nonsyndromic Craniosynostosis

  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 WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Nonsyndromic craniosynostosis (NCS) is a common, major structural birth defect - due to the premature fusion of one or more cranial sutures - that requires extensive surgical correction and is associated with considerable ongoing medical problems and health care costs. Because little is known about the causes of NCS, whole genome sequencing will help advance knowledge of genetic factors contributing to the etiology of NCS. Data from this project will lead to a better understanding of biological processes involved in the etiology of NCS and provide critical insights for development of early diagnostic tools and therapeutic strategies.

  Study phs001806

• Nanobody-Tethered Transposition Allows for Multifactorial Chromatin Profiling at Single-Cell Resolution

  Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility, and other factors. However, most current single-cell-resolution methods are unable to measure more than one aspect of chromatin state in a single experiment, limiting our ability to accurately measure chromatin states. Here we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), a new assay capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq utilizes recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk- and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and cells of the human immune system, demonstrating the high accuracy and sensitivity of the method. We further extend NTT-seq to enable simultaneous profiling of cell-surface protein expression alongside multimodal chromatin states to study cells of the immune system.

  Study phs003068

• Genetic Epidemiology of Ovarian Cancer Histotypes

  Epithelial ovarian cancer is a highly fatal malignancy with known genetic etiology; however, it is estimated that a substantial portion of narrow sense heritability remains to be discovered. The goal of this research was to use genetic information from distantly related ovarian cancer cases to identify regions of the genome that may harbor rare risk variants for epithelial ovarian cancer. The study was conducted in the setting of the Utah Population Database, a statewide data resource in which extensive ancestry data are linked to Utah Cancer Registry records. Focusing on families with a statistically significant excess risk of epithelial ovarian cancer, we used the Infinium Global Screening Array v.3.0 to generate germline genotyping data for distantly related cases. We then applied Shared Genomic Segment Analysis to each set of related cases to identify genomic regions that may harbor ovarian cancer risk variants. Eleven regions were identified. Genotype data are available through dbGaP for one case from each pedigree. Genotype data from other ovarian cancer cases within the high-risk pedigrees as well as the pedigrees' corresponding structures can be requested and made available with approval from the Utah Resource for Genetic and Epidemiologic Research (RGE).

  Study phs003140

• Genomics of Circulating Tumor Cells

  Comprehensive analyses of cancer genomes in clinical settings promise to inform prognoses and guide the deployment of precise cancer treatments. A major barrier, however, is the inaccessibility of adequate metastatic tissue for accurate genomic analysis in prostate and other cancers. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple technical hurdles. Here, we report an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of over 99.995% of the territory accessible in bulk exome sequencing is possible in CTCs. We validated our sequencing process in two prostate cancer patients including one for whom we compared CTC-derived mutations to mutations found in a lymph node metastasis and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early trunk mutations and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

  Study phs000717

• KRT17High/CXCL8+ Tumor Cells Display Both Classical and Basal Features and Regulate Myeloid Infiltration in the Pancreatic Cancer Microenvironment

  Recent studies have uncovered the co-existence of basal and classical subtypes within pancreatic ductal adenocarcinoma (PDAC). We sought to characterize these intermediary cells using single-cell RNA sequencing of PDAC. We performed subtyping on 18 single-cell RNA sequencing human PDAC samples to identify multiple intermediary subtypes. We compared single-cell profiling of patient-matched blood and tumor samples to measure changes in the local and systemic immune microenvironments in CXCL8-high tumors vs. CXCL8-low tumors. Finally, we leveraged longitudinally patient-matched blood over the course of chemotherapy. In our studies we identified a cluster of KRT17high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines which in turn influence the myeloid compartment both locally and systemically. We utilized sequencing data from dbGaP study accession phs002070. In addition to that, we included sequencing from new specimens which are deposited to this submission, consisting of one additional tumor specimen and 5 PBMC samples, sequenced after chemotherapy (longitudinally matched to PBMC samples in phs002071.v1.p1). FASTQ files of these sequencing runs are available through this dbGaP submission.

  Study phs003436

• Human Blastocyst 10X Single Cell RNA Sequencing

  Recent advances in human blastoids have opened new avenues for modeling early human development and implantation. One limitation of our first protocol for human blastoid generation was relatively low efficiency. We now report an optimized protocol for the efficient generation of large quantities of high-fidelity human blastoids from naive pluripotent stem cells. This enabled proteomics analysis that identified phosphosite-specific signatures potentially involved in the derivation and/or maintenance of the signaling states in human blastoids. Additionally, we uncovered endometrial stromal effects in promoting trophoblast cell survival, proliferation, and syncytialization during co-culture with blastoids and blastocysts. Side-by-side single-cell RNA sequencing revealed similarities and differences in transcriptome profiles between pre-implantation blastoids and blastocysts, as well as post-implantation cultures, and uncovered a population resembling early migratory trophoblasts during co-culture with endometrial stromal cells. Our optimized protocol will facilitate broader use of human blastoids as an accessible, perturbable, scalable, and tractable model for human blastocysts. In addition, this study is the first to use the 10X Genomics platform for human blastocysts, and we anticipate this resource will be widely used by the community as a reference for future studies.

  Study phs003122

• The taxonomic composition of the human microbiome of CRC patients and healthy donors

  In this study, single homogenized human stool samples from five healthy donors and one CRC patient were analyzed by shotgun sequencing to generate a baseline for the establishment of humanized microbiome to be transferred into mice. Briefly, fecal DNA was isolated from these samples using the DNeasy PowerSoil DNA Isolation Kit (Qiagen), according to the kit manual, except that samples were homogenized using the TissueLyzerII for five minutes at 40Hz instead of intense vortexing. The extracted DNA was further purified and concentrated using the DNA Clean and Concentrator Kit (Zymo Research). This DNA was thawed and refrozen once at -80°C for 16s sequencing before being thawed again for WGS. 200 ng of DNA was used for metagenomic library preparation using the Next Generation Sequencing DNA Library Prep Kit (Westburg), according to the user manual using an average insert size of libraries of 450 base pairs. Following quantification and quality control (Qubit® dsDNA BR Assay Kit (Thermofisher Scientific); Bioanalyzer High Sensitivity DNA Analysis Kit (Agilent Technologies)), sequencing was performed on a NextSeq500 instrument using 2×150 base pair read lengths.

  Study EGAS50000000759

• Biased allelic expression in human primary fibroblast single cells.

  The study of gene expression in mammalian single cells using genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We have used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblast cells over 133,633 unique heterozygous single nucleotide variants (hetSNVs). We have observed that at the snapshot of analyses each cell contains mostly transcripts from one allele from the majority of genes; indeed 76.4% of the hetSNVs display stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibit haplotype consistent allelic ratio; in contrast distant sites located in two different genes are independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in majority of the single cells at a given time point are rare and enriched in highly expressed genes. The relative abundance of each allele in a cell is controlled by some regulatory mechanisms since we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability.

  Study EGAS00001001009

• Global Anaplastic Thyroid Cancer Initiative

  Thyroid cancer is the most common endocrine malignancy. Most thyroid cancers are of the well-differentiated (non-aggressive) phenotype, and are almost always cured with standard treatments. In contrast, anaplastic thyroid cancer (ATC) is rare, accounting for only 1% of thyroid cancers, however it is perhaps the most lethal human malignancy with an average survival of 3 to 6 months. ATC presents with dramatic and rapid onset of airway and esophageal blockage with frequent spread to the lungs. Interestingly, 21–79% of ATCs have coexisting areas or a previous history of well-differentiated cancers. Although this suggests a progression from well-differentiated cancers to ATC, to date there is little molecular conformation that such a progression exists versus de novo generation of ATC. As ATC is extremely rare and most cases are inoperable, there are a paucity of tissue samples for study at any one center. The Global Anaplastic Thyroid Cancer Initiative (GATCI) aims to unite international institutions in order to pool samples (ATC with or without a paired well-differentiated component) for a comprehensive analysis of the genomic landscape of this disease.

  Study EGAS00001002234

• scRNA-seq of HSPC treated with gemcitabine and carbplatin

  The study used cryopreserved hematopoietic stem and progenitor cells (HSPCs) harvested from one patient with chronic myelogenous leukemia (CML). The cells were thawed and acclimatized for 48 hours in StemMACS HSC Expansion Media XF (Miltenyi Biotec) supplemented with StemMACS HSC Expansion Cocktail (Miltenyi Biotec) at 37°C in a humidified atmosphere containing 5% CO2. 4 samples of 2000000 HSPCs in 2 ml media each were then prepared and treated for 24 hours: carboplatin-high: 150 µg/ml carboplatin carboplatin-low: 18.75 µg/ml carboplatin gemcitabine: 25 ng/ml gemcitabine control: no drug Single-cells were subsequently extracted using the ddSEQ™ Single-Cell Isolator (Bio-Rad) and later sequenced using the SureCell™ Whole Transcriptome Analysis 3' Library Prep Kit (Illumina) on the NextSeq 500 System (Illumina) using the NextSeq 500/550 High Output Kit v2.5 150 Cycles (Illumina) all following the manufacturer's instructions. FASTQ-files were then processed following the ddSeeker (Romagnoli, D., et al., BMC Genomics 2018, doi:10.1186/s12864-018-5249-x) and Drop-seq (Macosko, E.Z., et al., Cell 2015, doi:10.1016/j.cell.2015.05.002) protocols for processing scRNA-seq data to yield the final digital gene expression for each cell.

  Study EGAS00001004381

• The Dynamic Landscape of Open Chromatin During Human Cortical Neurogenesis

  Non-coding regions comprise most of the human genome and harbor a significant fraction of risk alleles for neuropsychiatric diseases, yet their functions remain poorly defined. We created a high-resolution map of non-coding elements involved in human cortical neurogenesis by contrasting chromatin accessibility and gene expression in the germinal zone and cortical plate of the developing cerebral cortex. To obtain a high resolution depiction of chromatin structure and gene expression in developing human fetal cortex, we dissected the post-conception week (PCW) 15-17 human neocortex into two major anatomical divisions to distinguish between proliferating neural progenitors and post mitotic neurons: (1) GZ: the neural progenitor-enriched region encompassing the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ) and (2) CP: the neuron-enriched region containing the subplate (SP), cortical plate (CP), and marginal zone (MZ). Tissues were obtained from three independent donors and three to four technical replicates from each tissue were processed for ATAC-seq to define the landscape of accessible chromatin and RNA-seq for genome-wide gene expression profiling.

  Study phs001438

• Genomic and Transcriptomic sequencing of neuroblastoma patient

  Genomic and Transcriptomic single-cell sequencing of neuroblastoma patient. Data represents one 96-well plate that was processed with G&T sequencing, resulting in genomic and transcriptomic data from the same single cells. Dataset contains 95 bam files containing the DNA sequencing data and 95 bam files containing the RNA sequencing data.

  Dataset EGAD50000000728

• APP p.V742L and control fibroblasts RNA-seq

  This dataset consists of 16 FASTQ file pairs containing 3` RNA-sequencing data of patient-derived fibroblasts and three age- and sex-matched control fibroblast lines (CTR1, CTR2, and CTR3). The patient and CTR1 fibroblast lines have three biological replicates, while CTR2 and CTR3 lines both have one sample. Each sample has two lanes.

  Dataset EGAD50000001825