Search Results - EGA European Genome-Phenome Archive

Annotated VCF Files for WGS of ASD Cohort with 68 Individuals from 22 families, enriched for recent shared ancestry

We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. Samples were sequenced using Illumina HiSeq X platform, and Variants (single nucleotide variants (SNVs) and insertions or deletions (indels)) were detected using GATK with HaplotypeCaller. Quality control checks for (i) duplicate samples, (ii) samples per platform, (iii) genome call rate, (iv) missingness rate, (v) singleton rate, (vi) heterozygosity rate, (vii) homozygosity rate, (viii) Ti/Tv ratio, (ix) inbreeding coefficient, and (x) sex inference were performed as previously described. Variant call format (VCF) files for SNVs and indels were annotated with ANNOVAR using allele frequencies from the 1000 Genomes project (2015; 1000G), the Genome Aggregation Database (gnomAD), and the Greater Middle East Variome Project (GME).

Dataset EGAD00001008634

Blood neutrophils in COPD derive from activated progenitors in the bone marrow

Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

Dataset EGAD00001008788

Spatial multi-omic map of human myocardial infarction

We applied an integrative single-cell genomics strategy with single nucleus RNA sequencing (snRNA-seq) and single nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) together with spatial transcriptomics from the same tissue mapping human cardiac cells in homeostasis and after myocardial infarction (MI) at unprecedented spatial and molecular resolution. We profiled in total 31 samples from 23 patients including four non-transplanted donor hearts as controls and samples from tissues with necrotic tissue areas (ischemic zone, IZ), border zone (BZ), and the non-affected left ventricular myocardium (remote zone, RZ) of patients with acute MI.

Dataset EGAD00001008952

Blood neutrophils in COPD derive from activated progenitors in the bone marrow sc Seqwell

Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

Dataset EGAD00001008908

Blood neutrophils in COPD derive from activated progenitors in the bone marrow sc Rhapsody

Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

Dataset EGAD00001009704

Single-cell RNA sequencing of SarBC-01 treated with Dexamethasone vs DMSO, with or without Matrigel.

This dataset contains raw FASTQ files from single cell RNA sequencing of SarBC-01 cells treated with Dexamethasone vs DMSO, with or without Matrigel, processed with MULTI-seq. Cells from 4 different culture conditions (+Mat/Dex, +Mat/DMSO, -Mat/Dex, -Mat/DMSO) were harvested, processed for multiplexing using the MULTI-seq protocol and loaded in a Chromium Single Cell 3ʹ GEM Library and Gel Bead Kit v3 (10x Genomics). Gene expression (cDNA) and MULTI-seq libraries were prepared according to the manufacturers’ protocol of Chromium Next GEM Single Cell 3’ reagents Kits v3.1 (Dual Index). Finally, cDNA and MULTI-seq libraries were analyzed using an Agilent Bioanalyzer (DNA High Sensitivity kit) and sequenced on a NovaSeq6000 (S2 flow cell) platform. MULTISEQ BARCODES: TTAGCCAG => Matrigel/DMSO CCACAATG => Matrigel/Dexamethasone GCACACGC => noMatrigel/DMSO AGAGAGAG => noMatrigel/Dexamethasone

Dataset EGAD00001011155

The G2 gene expression signature and MYC overexpression are independent poor prognostic factors in childhood high-grade osteosarcoma

Key objective Are the prognostic transcriptomic G1/G2 gene expression signature, MYC overexpression, and MYC amplification replicable stratifying biomarkers for future clinical trials in high-grade osteosarcoma? Knowledge gathered In an unselected cohort, the G2 gene expression signature and MYC overexpression, but not MYC amplification, were independently associated with poor event-free and overall survival. Relevance Transcriptomic biomarkers may serve as stratifying factors that guide the management of patients with high-grade osteosarcoma. Current data underlines the importance of prospective validation of the G1/G2 signature and MYC overexpression in an international, multicenter, study.

Dataset EGAD00001015502

Slim Initiative in Genomic Medicine for the Americas (SIGMA): Mexico City Diabetes Study (MCDS)

The ~52,000 sample Type 2 Diabetes Exome Sequencing project is a collaboration of six consortia with various funding mechanisms that have joined together to investigate genetic variants for type 2 diabetes (T2D) using the largest T2D case/control sample set compiled to date. This includes samples from: Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Genetics of Type 2 Diabetes (GoT2D) Exome Sequencing Project (ESP) Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D) Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCAMP) Progress in Diabetes Genetics in Youth (ProDIGY) This data generated from the SIGMA Mexico City Diabetes Study was part of the Slim Initiative in Genomic Medicine for the Americas: Type 2 Diabetes (SIGMA T2D), which is an international research consortium funded by the Carlos Slim Foundation that seeks to identify the genetic risk factors for type 2 diabetes (T2D) in Mexico and Latin America and translate those findings into improved treatment and prevention of diabetes. The SIGMA T2D project has sequenced and genotyped more than 13,000 samples from Mexican and Mexican Americans. The individuals were obtained from over 20 cohorts across the 6 consortia that are listed in Table 1. The strategy was to perform deep exome sequencing of individuals, 24,991 with T2D and 24,953 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. The T2D-GENES, ProDIGY and SIGMA studies, sequencing was performed at the Broad Institute using the Agilent v2 capture reagent or Illumina Rapid Capture on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, two of the cohorts below are not in dbGaP, due to the samples not being consented for deposition. This includes the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study and Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) study. The Exome Sequencing Project (ESP) was deposited in dbGaP as part of their initial study and the phs numbers for that project can be found here: https://esp.gs.washington.edu/drupal/dbGaP_Releases Table 1. 52,000 sample T2D Case/Control Whole Exome Sequencing Studies Ancestry Consortia Study Countries of Origin # Cases # Controls African American T2D-GENES Project 1 Jackson Heart Study US 500 526 African American T2D-GENES Project 1 Wake Forest School of Medicine Study US 518 530 African American ESP Exome Sequencing Project (ESP) US 467 1374 African American T2D-GENES Follow up study BioMe Biobank Program (BioMe) US 1297 1256 East Asian T2D-GENES Project 1 Korea Association Research Project Korea 526 561 East Asian T2D-GENES Project 1& Follow up Study Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 1486 1568 East Asian T2D-GENES Follow up study Korea SNUH South Korea 450 475 East Asian T2D-GENES Follow up study Research Studies in Hong Kong (Hong Kong) Hong Kong 493 485 European T2D-GENES Project 1 Ashkenazi US, Israel 506 355 European T2D-GENES Project 1 Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European GoT2D Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European GoT2D Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European GoT2D UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European GoT2D Malmo-Botnia Study Finland, Sweden 478 443 European LuCamp Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention, and Care (LuCamp) Denmark 997 997 European ESP Exome Sequencing Project (ESP) US 390 2843 European T2D-GENES Follow up study Genetics of Diabetes and Audit Research Tayside Study (GoDARTS) Scotland, UK 960 966 European T2D-GENES Follow up study Framingham Heart Study (FHS) US 396 596 Hispanic T2D-GENES Project 1 San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 218 Hispanic T2D-GENES Project 1 & SIGMAv2 Starr County, Texas US 1762 1738 Hispanic SIGMAv1 Mexico City Diabetes Study Mexico 281 549 Hispanic SIGMAv1 & v2 Multiethnic Cohort (MEC) US 1476 1443 Hispanic SIGMAv1 & v2 UNAM/INCMNSZ Diabetes Study (UIDS) Mexico 1998 1977 Hispanic SIGMAv1 & v2 Diabetes in Mexico Study (DMS) Mexico 1522 1546 Multi ethnic ProDIGY Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) US 3097 0 Multi ethnic ProDIGY SEARCH for Diabetes in Youth (SEARCH) US 553 0 South Asian T2D-GENES Project 1 London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 531 538 South Asian T2D-GENES Project 1 & Follow up study Singapore Indian Eye Study Singapore (Indian Asian) 1640 1478 South Asian T2D-GENES Follow up study Pakistan Genomic Resource (PGR) Pakistan 914 932

Study phs001375

T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS)

The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to type 2 diabetes in multiple ethnic groups using next generation sequencing. To fulfill this objective, T2D-GENES Consortium undertook two large sequencing studies, called T2D-GENES Projects 1 and 2. Project 1 has carried out whole exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 non-diabetic controls, equally divided among five continental ancestry groups: Europeans, East Asians, South Asians, Hispanic Americans, and African Americans. The goal of Project 1 is to identify all genetic variants in the complete coding regions of the genomes (i.e., whole exome) by sequencing, including rare variants. Project 2 (i.e., SAMAFS substudy 2) is a pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence information from approximately 600 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas, augmented with family-based imputation into approximately 440 additional family members. The major objectives of Project 2 are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. Both T2D-GENES Projects 1 and 2 involve the San Antonio Mexican American Family Studies (SAMAFS), which are composed of four San Antonio, Texas-based family studies: the San Antonio Family Heart Study (SAFHS), San Antonio Family Diabetes/Gallbladder Study (SAFDGS), Veterans Administration Genetic Epidemiology Study (VAGES), and Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) Component and its extension called the Extended FIND [E-FIND]. The SAFHS and SAFDGS began in 1991 and have followed participants with extensive clinical phenotyping related to T2D for over 20 years. The VAGES was initiated in 1994 and a large battery of T2D-related phenotypic data has been obtained from its participants. The FIND-SA began in 2000, a part of the multicenter FIND study which was designed to identify genetic determinants of diabetic kidney disease; data from its participants related to T2D were used for this project. Non-overlapping subsets of SAMAFS participants are part of the T2D-GENES Projects 1 and 2, henceforth referred to as SAMAFS substudies 1 and 2, respectively. The SAMAFS substudies 1 and 2 are part of one of the five awards funded by NIDDK under a cooperative agreement award mechanism, which is governed by the Steering Committee of the T2D-GENES Consortium. Since Project 1 relies on population based subsets of cases and controls, 491 unrelated participants are drawn from the four SAMAFS as part of the T2D-GENES Project 1 Mexican American sample (i.e., SAMAFS substudy 1). The whole exome sequencing was performed at the Broad Institute. For Project 2, 1048 individuals are drawn from two SAMAFS (SAFHS and SAFDGS), representing 20 large families for substudy 2. The substudy 2 strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The available sample of 1,048 includes 5 sequenced individuals who do not belong to any of the 20 large pedigrees. The final family data of 1,043 individuals includes whole genome sequence data for 607 individuals. After quality control, 590 sequenced individuals provide data for family based imputation using Merlin linkage analysis software into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. The complete SAMAFS data including phenotype, genotype, sequence, other T2D-related trait data utilized for Projects 1 and 2 are available. These data can readily be viewed by clicking on the substudy title shown below or in the box: "Substudies", located on the right hand side of this parent or top study page phs000847.v1.p1, titled T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS). phs000849 T2D-GENES Project 1: San Antonio Mexican American Family Studies (SAMAFS), Substudy 1: Whole Exome Sequencing phs000462 T2D-GENES Project 2: San Antonio Mexican American Family Studies (SAMAFS), Substudy 2: Whole Genome Sequencing in Pedigrees

Study phs000847

LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

Study phs001405

NIDDK IBD Genetics Consortium Ulcerative Colitis Genome-Wide Association Study

This dataset contains data for 1,028 white, non-Hispanic, European ancestry individuals with ulcerative colitis who were included in a genome-wide association study published by Silverberg et al. (2009). These individuals were ascertained in North America and selected to have either left-sided or extensive disease (i.e., individuals with proctitis only were excluded). Genotyping was performed using the Illumina HumanHap300v2 (n = 540) and HumanHap550v3 (n = 488) Genotyping BeadChips at the Feinstein Institute for Medical Research. Control data (not included) were obtained from the NIDDK IBD Genetics Consortium's Crohn's Disease GWAS (available from dbGaP) and from studies 64 and 65 deposited in the Illumina iControlDB. Seven hundred eighty individuals in this dataset were taken from the NIDDK IBD Genetics Consortium cell line repository (http://www.niddkrepository.org). These individuals are identified in the file dbGaP_SubjectDS.txt. The subject IDs for these individuals may be used to request corresponding samples for follow-up research through the repository. In addition, complete phenotype data for these individuals are included, collected using the Consortium's forms and phenotyping manual (both included). The remaining 248 individuals were identified from pre-existing collections ascertained by members of the Consortium or their collaborators. For these samples, several of the items in the phenotype file are incomplete. Those who wish to replicate the results in Silverberg et al. should note that 6 individuals with missing genotype rates > 0.07 were excluded from that analysis (leaving 1,022 affected samples total). In addition, the minor allele frequencies (MAFs) reported in the publication were calculated using only those individuals who were included in the allelic association tests (n = 977 for SNPs included in the HumanHap300 and n = 476 for SNPs included only in the HumanHap550). These tests were performed using conditional logistic regression on gender-ancestry strata; individuals who were not placed in a stratum (using the procedure described in the supplementary information for Silverberg et al.) were excluded. The indicator variables hh300 and hh550 in the file dbGaP_PhenotypeDS.txt identify the samples included in the allelic association tests, and may be used to replicate the published MAFs among affected individuals.

Study phs000345

CTN - 0051: Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT)

The overarching goal of CTN-0051 is to foster adoption of new relapse-prevention pharmacotherapies in community-based treatment programs (CTPs) where these could have a substantial public health impact. To this end CTN-0051 will assess the comparative effectiveness of extended-release injectable naltrexone (XR-NTX, Vivitrol®), an opioid antagonist recently approved and indicated for the prevention of relapse to opioid dependence, versus buprenorphine-naloxone (BUP-NX, Suboxone®), a high affinity partial agonist indicated for maintenance treatment of opioid dependence, as pharmacotherapeutic aids to recovery. The study is conducted in 8 CTN-affiliated CTPs that provide or partner with detoxification services (inpatient/residential) which have the capacity to maintain participants opioid-free for approximately 3-7 days, have the capacity to provide medication-assisted therapy, and can provide a minimum of one group or individual counseling session per week during the 24-week treatment period. Up to 600 eligible participants will be randomized to treatment with XR-NTX or BUP-NX for 24 weeks (sufficient to include 350 participants who are randomized more than 72 hours after their last opioid). To maximize generalizability, the point of randomization is flexible, from shortly after program admission until just prior to program discharge. The primary goal of the study is to estimate the difference, if one exists, between XR-NTX and BUP-NX in the distribution of the time to relapse (i.e., loss of persistent abstinence) during the 6-month trial. The primary outcome measure is the time to the event, with the event called relapse. Secondary objectives are to: (1) compare outcome on XR-NTX versus BUP-NX across a range of clinical safety and secondary efficacy domains, (2) explore demographic, clinical, and genetic predictors of successful treatment and moderators of differential effectiveness (i.e., what variables may help clinicians choose which of these treatments is best for a given patient), and (3) collect a limited dataset to permit analyses of economic costs and benefits of the two treatments.

Study phs002876

Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

Study phs002514

Diabetic Retinopathy Genomics Study (DRGen) - Genetic Biomarkers of Diabetic Retinopathy

Using a well-defined, clinically supported phenotypic strategy, we seek to better understand the role of common and rare genetic variants in the progression of diabetic retinopathy (DR). Whole exome/whole genome sequencing (WES/WGS) was used to systematically search the human genome to detect DR susceptibility genes or genes that protect people from developing advanced DR. Clinical data and bio specimens were obtained from clinically defined DR phenotypes such as, (i) No/Mild NPDR (non-proliferative DR) with a subset of extreme phenotype, ii) Diabetic macular edema (DME) alone and iii) Proliferative diabetic retinopathy (PDR) alone. In this ongoing comprehensive genomic study, we wish to i) Identify potential common and rare variants that may influence the phenotypic differentiation of DR into DME or PDR, ii) Define genetic variants stratified based on the "extreme phenotype," and iii) Characterize genetic factors that determine the differential response to anti-VEGF drugs in DME patients. Definition of Diabetic Retinopathy and classification of groups Study 1. Proliferative diabetic retinopathy (PDR). Anybody showing evidence of retinal neovascularization on the disc (NVD) or elsewhere (NVE) with or without pre-retinal and vitreous hemorrhage will be considered PDR. We will include only those "active" PDR patients. The total number of consented subjects in this study is 182. Study 2. Isolated Phenotype: Varied response with anti-VEGF treatment is a significant limiting factor for better clinical outcomes. We quantify the response to anti-VEGF treatment based on visual acuity changes and anatomic features of DME assessed by optical coherence tomography (OCT). Depending on the response at one month following three monthly intravitreal anti-VEGF injections, we have observed two phenotypes: 1) Good responders: Participants were considered "good responders" if the anatomical outcome to anti-VEGF treatment resulted in a significant reduction of baseline central retinal thickness (CRT) > 25% after three anti-VEGF injections. 2) Poor Responders: Participants were classified as "poor responders" if the outcome of anti-VEGF treatment resulted in a reduction of CRT < 20% or in any increase in CRT after three monthly injections. The total number of consented subjects in this study is 17.

Study phs002501

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial

The IMagyn050 trial (NCT03038100), which evaluated the efficacy of Atezo vs placebo (Pla) with carboplatin, paclitaxel and bevacizumab (CPB) in front line ovarian cancer patient (pts), did not meet its co-primary endpoints of PFS in ITT or PD-L1+ (Moore et al. JCO 2021). The aim of this exploratory study was to evaluate whether patients with BRCA1/2-mutated or homologous recombination-deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. PD-L1 status of tumor-infiltrating immune cells was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates. Results Among biomarker-evaluable samples, 22% (234/1050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1024) had TMB ≥10 mut/Mb and 0.3% (3/1022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on immune cells) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. Conclusion Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.

Study EGAS00001006838

Single cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia.

Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10 to 20 genomic lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34+CD38- multipotent progenitor cells for 4 T-ALL cases. Hierarchical clustering detected a dominant leukemia clone at diagnosis, accompanied by a few subclones harboring only a fraction of the mutations. We developed a graph-based algorithm to determine the order of mutation acquisition. Two of the four patients had an early event in a known oncogene (MED12, STAT5B) amongst various pre-leukemic events. Intermediate events included loss of 9p21 (CDKN2A/B) and acquisition of fusion genes, while NOTCH1 mutations were typically late events. Analysis of CD34+CD38- cells and myeloid progenitors revealed that in half of the cases somatic mutations were detectable in multipotent progenitor cells. We demonstrate that targeted single cell sequencing can elucidate the order of mutation acquisition in T-ALL and that T-ALL development can start in a multipotent progenitor cell.

Study EGAS00001002830

BMP4 and temozolomide synergize in the majority of patient derived glioblastoma cultures

The poor prognosis of patients with glioblastoma is partly due to resistance to standard treatment, which combines chemoradiation using temozolomide (TMZ). The concept of cancer stem cells provided new insight into tumor resistance and management, and isolated Glioblastoma stem-like cells (GSCs) which contribute to this therapy resistance. Bone morphogenetic protein 4 (BMP4) is a differentiation factor that stimulates astroglial differentiation of such GSCs, thereby reducing their self-renewal. Exposing GSCs to BMP4 could therefore sensitize them to chemotherapy with TMZ, but previous studies with various treatment paradigms have produced contradictory results in this matter. Therefore, we re-defined the optimal treatment paradigm for the combination of TMZ and BMP4 and subsequently re-assessed the inter-tumoral variability in response to co-treatment with TMZ+BMP4 in vitro. First, the simultaneous treatment was found more effective than sequential therapy. Second, after application of our optimized treatment protocol, 70% of a total of 20 patient-derived glioblastoma cultures showed synergy when the treatments were combined. The synergistic effect was a result of increased cellular apoptosis and not of decreased proliferation. Comparative RNA-sequencing suggested that combination treatment results in decreased MAPK signaling. We conclude that addition of BMP4 to standard therapy with TMZ could enlarge the group of patients with good therapeutic response.

Study EGAS00001007095

Cell culture differentiation and proliferation conditions influence the in vitro regeneration of the human airway epithelium

The human airway mucociliary epithelium can be recapitulated in vitro using primary cells cultured in an Air-Liquid Interface (ALI), a reliable surrogate to perform pathophysiological studies. As tremendous variations exist between media used for ALI-cultured human airway epithelial cells, our study aimed to evaluate at a single-cell level the impact of several media (e.g. BEGMTM, PneumaCultTM, “Half&Half” and “Clancy”) on cell type distribution. Our work revealed the impact of these media on cell composition, gene expression profile, cell signaling or epithelial shape. We found higher proportions of multiciliated cells in PneumaCultTM-ALI and Half&Half, stronger EGF signaling from basal cells in BEGMTM-ALI, differential expression of the SARS-CoV-2 entry factor ACE2, and distinct secretomes transcripts depending on media used. We also established that proliferation in PneumaCultTM-Ex Plus favored secretory cells fate, showing the key influence of proliferation media on late differentiation epithelial characteristics. Altogether, our data offer a comprehensive repertoire for evaluating the effects of culture conditions on airway epithelial differentiation and will help to choose the most relevant medium according to the phenomenon to be investigated such as cilia or mucus biology or viral infection. We detail useful parameters that should be explored to document airway epithelial cell fate and shaping.

Study EGAS00001007572

Single cell transcriptional characterization of human megakaryocyte lineage commitment and maturation

Single cell RNA-sequencing of sternal bone marrow reciding Hematopoietic Stem Cells (HSCs) and Megakaryocytes (MKs) from individuals undergoing elective open heart valve replacement. HSCs were defined as Lineage-, CD34+, CD38-, CD45RA-, CD90+, CD49f+ cells. MKs where CD41a+, CD42b+ and ploidy was determined with Hoechst. A sternal bone marrow scraping was taken directly following median sternotomy using a Volkmann’s spoon. The sample was collected into an EDTA Vacutainer tube containing 1.8mg/ml EDTA. 4mL of Dulbecco’s phosphate buffered saline (PBS, Sigma) containing 10% human serum albumin (HSA, Gemini Bio Products) was added and the whole volume was resuspended by pipetting 2-3 times. The sample was then put on metallic thermal beads (ThermoFisher Scientific) at a temperature between 0-4°C and transported to the University of Cambridge for further processing. For HSC isolation the cells were stained with the following antibody cocktail: PECy5 conjugated anti-lineage specific antibodies: CD2 (BD), CD3 (BD), CD10 (BD), CD11b (BD), CD11c (BD), CD19 (BD), CD20 (BD), CD56 (BD), biotinylated CD42b (Pab5, NHS Blood and Transplant, International Blood Group Reference Laboratory [IBGRL]), biotinylated GP6 (Pab5, NHS Blood and Transplant, International Blood Group Reference Laboratory [IBGRL]) used in combination with PECy5 conjugated streptavidin (Biolegend). Alexa Fluor 700 conjugated anti-CD34 (BD), PerCP-Cy5.5 conjugated anti-CD38 (BD), Pacific Blue conjugated anti-CD45RA (Invitrogen), PECy7 conjugated anti-CD90 (BD),PE conjugated anti-CD49f (BD). After staining cells were kept at 4°C before sorting using a FACS Aria Fusion flow sorter (BD). Single HSCs defined as Lineage-, CD34+, CD38-, CD45RA-, CD90+, CD49f+ cells were sorted by FACS directly into individual wells of a 96-well plate. Index sort data was collected for each single cell. For MK isolation the cells were stained for surface MK markers with mouse anti-human CD41a APC conjugated antibody (BD) and mouse anti-human CD42b PE conjugated antibody (BD) and for ploidy analysis with 1ug/ml Hoechst 33342 (Invitrogen). After incubation at 37°C for 30 minutes, the cells were kept at 4°C before sorting using a FACS Aria Fusion flow sorter (BD). Single cells and MK pools of 20 cells were sorted by FACS according to ploidy level using a 100uM nozzle directly into individual wells of a 96-well plate. cDNA synthesis and poly(A) enrichment was performed following the G&T-seq protocol (Macaulay et al. 2015), a variation of the Smart-seq2 protocol1. ERCC spike-in RNA (Ambion) was added to the lysis buffer in a dilution of 1:4,000,000.

Dataset EGAD00001006677

WES data (cfTrack study) from NSCLC patients and OC patients

We also collected samples from 8 NSCLC patients and 4 ovarian cancer patients and. For all 8 NSCLC patients, a tumor biopsy sample, a WBC sample, and three plasma samples were collected. For all 4 ovarian cancer patients, a WBC sample and two serum samples were collected. We collected tumor tissue sample from one ovarian cancer patient (OV4). The cfDNA was extracted from their plasma samples using the QIAamp circulating nucleic acid kit from QIAGEN (Germantown, MD). For serum cfDNA, ampure XP beads size selection was further performed to eliminate gDNA contamination. In brief, 0.5 volume of beads were first added to the cfDNA samples. After incubation, the supernatant was transferred to a new tube and an additional 2.0 volume of beads were added. After 80% ethanol wash, cfDNA was eluted from the beads. FA assays (Agilent Technologies) were performed to rule out the contamination of gDNA in the size selected samples. The cfDNA WES library of all patients and the genomic DNA WES library of the 4 ovarian cancer patients were constructed with the SureSelect XT HS kit from Agilent Technologies (Santa Clara, CA) according to the manufacturer’s protocol. In brief, 10ng of cfDNA was used as input material. After end repair/dA-tailing of cfDNA, the adaptor was ligated. The ligation product was purified with Ampure XP beads (Beckman-Coulter, Atlanta, GA) and the adaptor-ligated library was amplified with index primer in 10-cycle PCR. The amplified library was purified again with Ampure XP beads, and the amount of amplified DNA was measured using the Qubit 1xdsDNA HS assay kit (ThermoFisher, Waltham, MA). 700-1000 ng of DNA sample was hybridized to the capture library and pulled down by streptavidin-coated beads. After washing the beads, the DNA library captured on the beads was re-amplified with 10-cycle PCR. The final libraries were purified by Ampure XP beads. The library concentration was measured by Qubit, and the quality was further examined with Agilent Bioanalyzer before the final step of 2x150bp paired-end sequencing at an average coverage of 200. Whole-exome capture libraries of genomic DNA from the 8 NSCLC patients were constructed via Roche SeqCap EZ Exome V6 (Roche). Enriched exome libraries were sequenced on the Illumina HiSeq 3000 platform (Illumina) to generate 2x100bp paired-end reads at an average coverage of 200.

Dataset EGAD00001008454

HIV Viremic Non-Progressors (VNPs) and HIV Progressors Data Access Committee

Data Access Committe for the project: Analyzing exome sequencing in HIV Viremic Non-Progressors (VNPs) and HIV Progressors

Dac EGAC50000000062

CD4 auto-antigens

The CD4 auto-antigen Access Committee (DAC) manages and oversees data access, ensuring compliance with ethical and regulatory guidelines while facilitating secure sharing with authorized researchers.

Dac EGAC50000000864

scRNAseq data of HGSOC patients before and after treatment

Dataset EGAD50000000191

Whole exome sequencing of bulk primary tumor (and one lymph node metastasis) and matched blood of six non-metastatic breast cancer patients

Dataset EGAD00001002746

Wilms_Tumour_organoid_sequencing_WGS

This study investigates the genomic and transcriptomic characteristics of Wilm's tumour organoids

Study EGAS00001002692

The_mutational_landscape_of_recurrent_Glioblastome_multiforme

Targeted gene screen of approx 120 patients with primary GBM and recurrent samples.

Study EGAS00001001764

RNA-Seq and WXS from 6 glioblastoma patients

Dataset EGAD00001003293

IfGH-10772

Clinical and genetic information of an individual with RVOT-VT and a KCNK2 (TREK1) gene mutation obtained after whole exome sequencing.

Dataset EGAD00001003328

H3Africa NEEDI SNPs and INDELs

SNPs and INDELs of novel hereditary neurological disease genes in Mali using Beckman 8800, ABI 3730/3730xl.

Dataset EGAD00001006295

STAG1 and STAG2-ChIP-seq in RAD21-mutant adult acute myeloid leukemia

Dataset EGAD00001015361

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

Idiopathic Pulmonary Fibrosis Network AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (IPFNet-ACE-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: The ACE-IPF trial tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in Forced Vital Capacity (FVC) in subjects with Idiopathic pulmonary fibrosis (IPF).Background: IPF is a chronic, progressive lung disease of unknown cause characterized by the histopathologic pattern of usual interstitial pneumonia. The median survival of patients with IPF after the onset of symptoms is 2 to 5 years. Prior animal and human studies in pulmonary fibrosis provide a compelling rationale to examine anticoagulation as a therapeutic approach in IPF. Large epidemiologic studies link IPF with thrombosis-related clinical events, such as an increased risk of acute coronary syndrome and deep vein thrombosis. The suspected causal relationship may extend beyond simple coagulation cascade-induced thrombus formation, as procoagulant enzymes may directly stimulate fibrosis via cell surface receptor - mediated responses.Participants: Patients aged 35 to 80 years with progressive IPF were potentially eligible. Progressive IPF was defined as a history of (1) worsening of dyspnea, or (2) physiologic deterioration defined as an absolute decline of either FVC greater than or equal to 10% or DlCO greater than or equal to 15%, a reduction in arterial oxygen saturation of greater than or equal to 5%, or progression of radiographic findings. Between December 14, 2009 and April 1, 2011, 145 subjects were enrolled: 72 in the warfarin group and 73 in the placebo group. The mean age for the population was 67 years. 27% of the subjects were women and 92% were white.Participants were excluded if they met any of the following criteria: current indication for, or treatment with, warfarin, prasugrel, or clopidogrel combined with aspirin; the presence of an increased risk of bleeding; a recent cerebral vascular accident or gastrointestinal bleeding; any current signs or symptoms of severe, progressive, or uncontrolled comorbid illness; and their presence on the active list for lung transplantation. Design: ACE-IPF was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio (INR) of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. Study subjects were provided two strengths of warfarin tablets (1 mg and 2.5 mg) or matching placebos. Subjects measured their INR with encrypted meters at least weekly. Participants were seen at screening, baseline, and at 16, 32, and 48 weeks after enrollment. Home monitoring was validated by plasma INR measurement at the week 1 and 16 visits.The primary outcome was a composite endpoint based on the time to all-cause mortality; nonelective, nonbleeding hospitalization; or a decrease in the absolute FVC greater than or equal to 10% from baseline value. Secondary outcome measures included rates of mortality, hospitalization, respiratory-related hospitalization, acute exacerbation, bleeding, cardiovascular events, and changes over time in FVC, 6-minute walk test distance, DlCO, plasma fibrin D-dimer levels, and quality of life (QOL).Conclusions: The study did not show a benefit for warfarin in the treatment of patients with progressive IPF and was terminated due to excess mortality in the warfarin treatment group. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.Reported causes of death indicated 11 of the 14 were respiratory-related in the warfarin group versus three of the three in the placebo group. There were also three cardiovascular deaths in the warfarin group versus none in the placebo group. No deaths were attributed to bleeding. The warfarin group also demonstrated an increased rate of combined all-cause hospitalization and all-cause mortality. (Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95.)

Study phs004070

Gene Expression in an African American Schizophrenia Dataset

Schizophrenia is a common and severe psychotic disorder. While some common SNPs and rare copy number variants have been identified as being significantly associated with disease risk, the biological mechanisms remain largely undefined. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using RNAseq on lymphoblastoid cell lines from schizophrenia cases and controls of African American ancestry. Genes related to immune processes were enriched in the genes differentially expressed in the schizophrenia cases. Approximately half of the differentially expressed genes in this African American dataset were also differentially expressed by affection status in our previously studied European ancestry dataset (PMID: 28418402).

Study phs002842

FaceBase Study of Facial Shape in Tanzania: CIDR

The goals of this project are to identify loci that underlie major genetic determinants of orofacial shape, by means of a GWAS in a cohort of normal African children (from Tanzania) from whom we have collected 3D digitized facial morphometric scans, and a subsequent replication study of normal children from the same population. These studies are part of the NIDCR FaceBase initiative (https://www.facebase.org/). In addition to dbGaP, all study genotype and phenotype data (including primary facial scans and landmarks) will be available for data-sharing with qualified investigators via the NIDCR FaceBase Hub (www.facebase.org/), following approval by the NIDCR FaceBase Data Access Committee.

Study phs000622

Single-Cell RNA-Sequencing Analysis of Responses to Pembrolizumab in Sezary Syndrome

This phase 2 single arm clinical trial assessed the efficacy of pembrolizumab in patients with previously treated mycosis fungoides or Sezary syndrome. Pembrolizumab was found to have a 38% overall response rate, and a 27% overall response rate in subjects with Sezary syndrome. We performed single-cell RNA-sequencing on samples collected before the first treatment and after 3 weeks of pembrolizumab treatment. Sequencing was performed on cryopreserved peripheral blood T-lymphocytes isolated from 6 trial participants, including 3 patients who responded to pembrolizumab treatment and 3 patients who did not respond. A total of 118,961 peripheral blood T-cells are included in this data set.

Study phs002933

GWAS in Fibrosing Interstitial Lung Disease

This study was a case-control genome-wide association study of 1616 non-Hispanic white cases and 4683 controls. Under an additive model for the minor allele at each SNP, we identified 19 SNPs, representing 7 chromosomal locations (5p15, 6p24, 7q22, 11p15, 15q14-15, 17q21, and 19p13), with genome-wide significant (P < 5x10-8) associations using the discovery samples included in this submission. We genotyped the 19 genome-wide significant SNPs in addition to 178 SNPs with 5x10-8 < P-value <.0001 and found 4 additional loci (3q26, 4q22, 10q24, and13q34) with genome-wide significant SNPs in the meta-analysis.

Study phs000751

Massachusetts General Hospital/Eisai National Institute of Mental Health (NIMH) Genetics Initiative Alzheimer's Disease GWAS - Affymetrix GeneChip Human Mapping 500K Array Set

This study cohort was collected as part of the National Institute of Mental Health (NIMH) Alzheimer's disease Genetics Initiative Study. Recruitment of families, predominantly sibling, for the cohort was focused on local memory disorder clinics, nursing homes, and the surrounding community. Clinical evaluation was performed at the University of Alabama at Birmingham, Johns Hopkins University, and Massachusetts General Hospital/Harvard Medical School. Informed consent was obtained from all study participants, for participants with extensive cognitive impairment, a legal guardian or caregiver with power of attorney provided consent. To determine age of onset, a creditable informer was interviewed and medical records were evaluated.

Study phs000483

Genetics of Male Infertility Initiative (GEMINI)

The Genetics of Male Infertility Initiative (GEMINI) project is a multi-center study designed to discover and characterize genetic variants conferring risk for male infertility. Patients enrolled in GEMINI have been clinically diagnosed with male infertility. Patients are recruited from multiple medical centers and are primarily of European ancestry. DNA from each patient is extracted from peripheral blood or saliva and used for exome sequencing. Genetic data generated by the GEMINI project has contributed to the discovery of over a dozen genes involved in human infertility. A VCF file of genetic data from GEMINI patients that have been appropriately consented will be available through dbGaP.

Study phs003115

Lysosomal Disease Network (LDN6719) Immune Response to Intrathecal Enzyme Therapy in Mucopolysaccharidosis 1 Patients

In this study we characterized the immune response to intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis I (MPS I) subjects with spinal cord compression who had been previously treated with intravenous rhIDU. Concentrations of specific antibodies and cytokines were measured in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions. These serologic findings were compared with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms. We found that IT rhIDU was generally well tolerated in the subjects studied although one subject had moderate to severe clinical symptoms and serologic abnormalities consistent with an immune response.

Study phs000862

Genomics of Relapsed Small Cell Lung Cancer Progression

Small cell lung cancer (SCLC) accounts for nearly 15% of all patients with lung cancer. Though the response to initial therapy is favorable in many patients, a majority of patients go on to develop recurrent disease which is very difficult to treat. The response rates to chemotherapy are very low and most patients succumb to relapsed SCLC within a few months. Virtually no progress has been made in the treatment of SCLC in the last three decades. In order to better understand the molecular alterations in relapsed SCLC, we have generated exome and RNA sequence from normal, primary tumor and relapse tissues of SCLC patients.

Study phs001049

Contribution of systemic and somatic factors to clinical response and resistance in urothelial cancer: an exploratory multi-omic analysis

Patients with metastatic urothelial cancer (n=29) were treated with atezolizumab (anti-PD-L1). All 29 patients had T-cell receptor sequencing (TCR-seq) of the pre-treatment blood; 24 also had TCR-seq on at least one post-treatment blood sample. 24 patients had TCR-seq of their pre-treatment tumors. TCR-seq data can be found at http://doi.org/10.5281/zenodo.546110. 26 patients also had RNAseq of their tumors and whole exome sequencing (WES) of their tumors and matched normal blood. WES results for one sample were excluded from our analysis after failing to meet coverage requirements.

Study phs001743

Single-Cell Transcriptomic Characterization of Microscopic Colitis

Patients with microscopic colitis (MC), chronic diarrhea without histological signs of MC, or unaffected controls were profiled using single-cell RNA sequencing (scRNA-seq; inDrops and 10X Genomics were used). One profiled patient without clinical symptoms was found to have histological signs of MC (asymptomatic MC). Some of the subjects from dbGaP study phs003418 are controls in this study. T-Cell Receptor sequencing (TCR-Seq) was also performed on a subset of patients. Individual transcriptomes were analyzed to characterize the cellular profile associated with MC and search for mediators of disease pathology. Raw reads and processed count matrices will be available through dbGaP.

Study phs003876

COVID-19-Induced Immune Alterations in Infants

Although previous studies have described some overlap between COVID-19-induced immune alterations in adults and children, no systematic immune profiling studies have been reported in infants. We applied a multidimensional approach to decipher the immune responses to SARS-CoV-2 infected infants (n=26; 10 mild, 11 moderate and 5 severe) and healthy matched controls (n=14). Single-cell RNA-seq profiling (scRNA-seq) of PBMCs revealed alterations in cell composition upon infection, with most cell types demonstrating an interferon-stimulated gene (ISGhi) state. Our findings shed insight into the immune responses to SARS-CoV-2 in the first year of life.

Study phs002655

Evolution of Structural Rearrangements in Prostate Cancer Intracranial Metastases

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. We sought to characterize prostate cancer intracranial metastases in order to improve our understanding of their pathogenesis and to promote the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) on samples from 21 patients. The WGS samples include 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n=6) and non-brain prostate cancer metastases (n=26).

Study phs003357

Amplicon sequencing of melanoma samples

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

Study JGAS000351

Whole exome sequencing of familial MDS, Two patients

Although several causal genes of familial myelodysplastic syndromes (MDS) have been identified, the genetic landscape and the molecular pathogenesis are not totally understood. To explore novel driver genes and their pathogenetic significance, we performed whole exome sequence analysis of two individuals from a familial MDS pedigree and several candidate single-nucleotide variants were identified. Knockdown screening revealed that downregulation of a candidate gene enhanced colony forming capacity of primary murine bone marrow (BM) stem/progenitor cells. Our results indicate that a familial MDS-associated germline mutation in the candidate gene induces accumulation of DNA double-strand breaks, possibly through impaired PCNA polyubiquitination.

Study JGAS000162

Long-read single-cell RNA sequencing uncovers cell-type specific transcript regulation in COVID-19

SARS-CoV-2 infection leads to extensive host transcriptomic changes, but the role of alternative splicing in shaping the immune response remains underexplored. Here, we present the first application of long-read single-cell RNA sequencing on nasopharyngeal swabs from COVID-19 patients and healthy controls to resolve transcript-level changes across cell types. Leveraging the strengths of long-read sequencing, we characterize alterations in both gene and isoform expression within cell populations of the upper respiratory tract—the primary site of SARS-CoV-2 entry. This approach provides new insights into how transcriptional regulation and splicing shape host immune responses to viral infection.

Study EGAS50000001290

MorphoITH: A Framework for Deconvolving Intra-Tumor Heterogeneity Using Tissue Morphology

This study introduces MorphoITH, a framework for deconvolving intra-tumor heterogeneity (ITH) in clear cell renal cell carcinoma (ccRCC) based on tissue morphology from histopathological slides. The study tested MorphoITH's ability to capture different aspects of morphology and to reflect genetic ITH. The data deposited here is derived from a morphology guided multi-regional sequencing dataset used to study the relationship between morphology and genetic evolution. This dataset consists of whole exome sequencing of tumor from multiple sites and adjacent normal samples which were collected from two patients treated in affiliated hospitals of the University of Texas Southwestern Medical Center (UTSW), including Parkland Hospital.

Study EGAS50000001064

Investigating immunopathological signatures associated with COVID-19 severity post Omicron

The aim of this study was to investigate the type and duration of protective immunity alongside immunopathological signatures associated with COVID-19 severity. RNA sequencing was performed using the Illumina Stranded mRNA Prep Ligation kit to investigate the protein coding transcriptome of PBMC cells. T cell receptor (TCR) repertoire profiling was performed with the TakaraBio SMART-Seq Human TCR (with UMIs) on PBMC cells to investigate the depth and persistence of SARS-CoV-2 targeting TCRs. The cohort (n=20) consisted of 10 non-hospitalised and 10 Hospitalised individuals with samples analysed 3 months post positive SARS-CoV-2 PCR.

Study EGAS50000000926

plasma DNA LINE-1 targeted bisulfite sequencing: a new non-invasive multi-cancer detection marker

The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. We developed a PCR-based targeted bisulfite method coupled to deep sequencing to detect methylation patterns of L1PA elements,which we named DIAMOND (for Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA). We used sodium bisulfite chemical conversion to achieve base-pair resolution analysis and designed a multiplexed PCR based on 8 amplicons covering L1PAs .

Study EGAS50000000446

16792 results for "sec+and+unspecified+malignant+neoplasm"

in 53.98 milliseconds.