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• Targeted sequencing data of cfDNA, archival tissue, and WBC from 208 patients with mUC

  Targeted tissue (n=81), cfDNA (n=319), and WBC (n=208) Illumina sequencing of metastatic urothelial carcinoma patients. All cfDNA is collected in the metastatic setting, while archival tissue is from across the disease course. White blood cell (WBC) samples are used as patient matched germline samples. All files are in paired-end fastq format.

  Dataset EGAD50000002089

• All you need to know about our new DAC Portal v2

  An updated version to boost the management of DACs (Data Access Committees), policies, and data access requests. In September of 2023, we launched new services for all EGA users, including a DAC Portal. Since then, our team has been working to refine it and improve the user experience. The version 2 of our DAC Portal is now ready, with a range of new features aimed at streamlining your workflow and boosting productivity. If you are interested in learning more about the latest version of our DAC Portal, then you are in the right place! In this post, you will find information about the implemented features and more. The full documentation is available on our website. Moreover, we highly recommend exploring the DAC Portal through the Take the Tour. This said, let's get cracking! Customise your data access requests table This table offers the possibility to tailor information about the data access requests by making visible or hiding different columns regarding the Dataset Persistent Identifier, the Organisation or the requestor's name s, among others. You can choose which columns to see, depending on your needs and interests. Additionally, we have implemented two new features columns with two new functionalities, DAC Comment and Expiration Date. You can find more details in the following sections! In this table, all data access requests are displayed by default. With the latest version of the Portal, you can now apply filters, combine them, and save them for future use. Leave internal comments on pending requests and visible to all the DAC Members We understand that many Data Access Committees (DACs) cannot instantly approve or deny data access requests. Often, there's an intermediary phase where discussions and the signing of legal documents are necessary. To facilitate this process, we've introduced the DAC comment feature! When you navigate to the DAC column, you'll find two tabs: "User" and "DAC". Under "User", you'll see the message provided by the requester at the time of requesting access to the data. As a DAC member/admin, you can then add an internal comment in the "DAC" tab. These comments are visible only to DAC members/admins, ensuring confidentiality. Requesters won't have access to DAC comments. By adding a DAC comment to a pending request, we'll know that you've begun reviewing it. This allows you to filter pending requests without DAC comments to focus on genuinely new requests, and it prevents you from receiving email notifications about ongoing data requests. Set expiration dates for permissions and revoke them automatically The latest update to the DAC Portal introduces a new feature allowing you to set expiration dates for new access requests. For instance, if you anticipate approving a data access request but only wish to grant access for a limited time, you can now specify an expiration date for the granted permissions. Once this date is reached, the permissions will automatically be revoked. By default, permissions are granted indefinitely without an expiration date. However, if you ever need to revoke permissions, you can easily do so from the History page. Audit your metadata objects Managing and auditing your metadata objects will be easier from now on as the new DAC Portal enhances and facilitates your role as a Data Controller. This is possible thanks to the tables available in each of the primary tabs visible on the homepage: DACs, Policies and Datasets. Starting with DACs, this section allows to check the policies linked to a specific DAC. In Policies, you can obtain a list of the datasets connected to a particular policy. In the Dataset tab, it is possible to group datasets by either DAC or Policy, as well as the release status. Now you have the option of deprecating metadata objects that you don’t want to use anymore, or that were created by mistake. You will find the deprecate button on the EDIT page of the DAC, as well as for registered policies. You can find more information here. What's neat about this feature is that once a DAC or policy is deprecated, it becomes hidden within the DAC Portal. This ensures that you only see information that is consistently up to date! Define your preferences regarding email notifications For pending requests, you will be able to decide how often you want to get the notifications: daily, weekly or fortnightly. Remember, you will not receive email notifications for pending requests with a DAC comment! Furthermore, you have the flexibility to decide which notifications you wish to receive, such as invitations to join a new DAC or notifications regarding DAC acceptance by the Helpdesk, among other options. Check the User preference to see the complete list of available notification settings! What’s next: incoming DAC Portal API In addition to the new DAC Portal, we are excited to announce the release of the DAC API! This enables users to programmatically manage permissions. If you are interested in learning more about the technical specifications, you can consult the DAC API specification. This post was written by Aina Jené and Ana T. Alonso.

  Blog new-dac-portal-v2

• Xenodiagnosis of Lyme Disease

  Ixodes scapularis ticks are an important vector for at least six tick-borne human pathogens, including the predominant North American Lyme disease spirochete Borrelia burgdorferi. The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without excessive activation of the proinflammatory branch of the vertebrate immune system. While the ability for nymphal ticks to feed on a variety of hosts has been well-documented, the host-parasite interactions between larval I. scapularis and different vertebrate hosts is relatively unexplored. In our clinical trial, patients with prior Lyme disease who had completed antibiotic therapy were exposed to 25-30 laboratory-reared larval ticks. Skin biopsies were taken before tick placement and/or after ticks were allowed to feed to repletion and we examined the effects on the transcriptional profile of human skin after the larval tick bites. We note pronounced evidence of inflammation in humans.

  Study phs003314

• ALPI deficiency causes refractory Inflammation Bowel Disease

  Herein, we report the first identification of biallelic-inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

  Study EGAS00001003350

• EGA QuickView

  EGA QuickView Secure and Remote Access to EGA Files What is EGA QuickView? EGA QuickView is a FUSE file system that allows secure and remote access to EGA files. It is a hybrid of sshfs and crypt4ghfs, which means it uses ssh to connect to the EGA distribution servers, downloads data in Crypt4GH format, and transparently decrypts those files. It is compatible with Linux and macOS 12. Why use EGA QuickView? EGA QuickView is a highly useful and convenient tool for anyone who needs to access EGA files remotely and securely. The software offers a quick and convenient way to browse through EGA files without the need for complete downloads, thus saving bandwidth and time. Whether you are a medical professional requiring access to sensitive patient data or a research scientist working on a project that involves EGA files, EGA QuickView provides a highly useful solution. The software boasts advanced security features, ensuring that your data is safe and protected at all times. Get started with EGA QuickView To get started with EGA QuickView, visit the EGA QuickView GitHub repository for more information and installation instructions.

  Documentation access/download/visualisation/ega-quickview

• Direct Comparative Analysis of 10X Genomics Chromium and Smart-seq2

  Single cell RNA sequencing (scRNA-seq) is widely used for profiling transcriptomes of individual cells. The droplet-based 10X Genomics Chromium (10X) approach and the plate-based Smart-seq2 full-length method are two frequently-used scRNA-seq platforms, yet there are only a few thorough and systematic comparisons of their advantages and limitations. Here, by directly comparing the scRNA-seq data by the two platforms from the same samples of CD45- cells, we systematically evaluated their features using a wide spectrum of analysis. Smart-seq2 detected more genes in a cell, especially low abundance transcripts as well as alternatively spliced transcripts, but captured higher proportion of mitochondrial genes. The composite of Smart-seq2 data also resembled bulk RNA-seq data better. For 10X-based data, we observed higher noise for mRNA in the low expression level. Despite the poly(A) enrichment, approximately 10-30% of all detected transcripts by both platforms were from non-coding genes, with lncRNA accounting for a higher proportion in 10X. 10X-based data displayed more severe dropout problem, especially for genes with lower expression levels. However, 10X-data can better detect rare cell types given its ability to cover a large number of cells. In addition, each platform detected different sets of differentially expressed genes between cell clusters, indicating the complementary nature of these technologies. Our comprehensive benchmark analysis offers the basis for selecting the optimal scRNA-seq strategy based on the objectives of each study.

  Study EGAS00001003973

• Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL

  Next generation sequencing (NGS) data analyzed in Rivas-Delgado, López, et al. HemaSphere 2024. Single nucleotide variants (SNVs) and short insertions /deletions (indels) were evaluated in 42 samples using a B-cell malignancy-oriented targeted panel covering 115 genes (SureSelectXT, Agilent Technologies and sequenced in a MiSeq instrument (Illumina; 2x150bp; mean coverage of 599x). The NGS data of 39 samples is provided here. The 3 additional samples were previously published. Please, see the original publication for additional details.

  Study EGAS50000000521

• Genetic Epidemiology of Lung Cancer Consortium GWAS of Familial Lung Cancer

  Familial lung cancer cases were collected by the Genetic Epidemiology of Lung Cancer Consortium (GELCC) recruitment sites: University of Cincinnati, Karmanos Cancer Institute at Wayne State University, Louisiana State University Health Sciences Center-New Orleans, Mayo Clinic, and Medical College of Ohio. Familial cases for this study came from three sources: 1) one case each from families (at least 3 affected lung cancer cases in the family) included in the linkage analysis; 2) one case from linkage-eligible families (at least 3 affected lung cancer cases in the family) but where there were insufficient biospecimens available to make them informative for linkage analysis; and 3) one case from families not eligible for the linkage study with a family history of at least one first or second degree relative affected with lung cancer. Unrelated controls were selected from 1) among the spouses of family members, thus matching on socio-economic status (SES) and ethnicity (typically) of the cases or 2) from case-control studies of lung cancer conducted in the same location in which the linkage families were collected and matched on age, sex, and race. All cases and controls self-reported as European American. Biospecimens used for normal DNA extraction included blood, saliva or mouthwash. Some samples underwent whole genome amplication.

  Study phs000629

• The role of gut microbiota in metabolic diseases

  Diabetes is a major disease in the elderly and is responsible for increased risk of myocardial infarction and stroke. Recently, the relationship between microbiota and diabetes has been reported in animals and humans. In this study, blood, stool, and saliva samples were collected from examinees at the University of Tokyo Health Screening Center, and 16S rRNA and metagenomic analyses were performed to determine the variation of microbiota. Furthermore, metabolome analysis and transcriptome analysis (CAGE analysis) using blood were performed to reveal changes in host metabolites and gene expression. By comparing the host- and bacteria- derived information with the metabolic parameters, we analyzed whether microbiota can be a predictor of metabolic diseases.

  Study JGAS000569

• NHLBI TOPMed: My Life Our Future (MLOF) Research Repository of Patients with Hemophilia A (Factor VIII Deficiency) or Hemophilia B (Factor IX Deficiency)

  Hemophilia A and B are X-linked bleeding disorders resulting from a deficiency in coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Hemophilia affects approximately 1/5000 male births worldwide, and results in premature death and disability due to bleeding if coagulation factor replacement therapy is not used effectively. Hemophilia is clinically categorized by coagulation factor activity levels and ranges in severity from mild (6% to 30%) to moderate (1-5%) to severe (<1%). Many female "carriers" of hemophilia also have decreased factor activity and morbidity from bleeding. Hemophilia A and B are almost always caused by identifiable mutations in the F8 and F9 genes, respectively, and these mutations are found throughout the structural genes. Although the hemophilias are monogenic disorders, there are wide variations in disease severity and therapeutic outcomes which are not readily explained by the disease causing mutations alone. The My Life Our Future (MLOF) project (www.mylifeourfuture.org) is a national resource developed by a partnership of BloodworksNW (BWNW, formerly the Puget Sound Blood Center), the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF) and Bioverativ, to provide free F8 and F9 gene variant analysis to patients with hemophilia A or B, and to establish a research repository of DNA sequence, DNA, RNA, buffy coat, serum and plasma. The sequence analysis and serum samples are linked to a phenotypic database hosted by ATHN, with samples submitted and clinical data entered at ~100 hemophilia treatment centers (HTCs) nationwide. (See ATHN Research Report Brief in the resource center at www.athn.org). MLOF has become the largest hemophilia genetic project worldwide. The roles of the MLOF partners are: BWNW, to serve as the central laboratory for the project and house the research repository; ATHN, to support and provide the administrative link with HTCs, to facilitate the collection of accurate phenotypic data, to conduct research review and approval for use of the repository and with BWNW to provide samples and data for research projects; NHF, to provide consumer education and facilitate consumer input into the project; and Bioverativ, to provide financial support and scientific input. The project is governed by a Steering Committee consisting of one representative from each organization. Subject samples chosen from the MLOF parent study for TOPMed and WGS were drawn from those who gave (or parents gave) informed consent for the Research Repository and included patients of all severities and type, but with an emphasis on those with severe hemophilia and others at increased risk of neutralizing antibody (inhibitor) formation and who had samples in the Research Repository (plasma, serum, RNA) for potential additional -omic studies. Also included were samples from subjects where a likely causative variant for hemophilia was not found in the F8 or F9 coding region, intron-exon boundaries or immediate upstream and downstream regions. Since hemophilia is an X-linked disorder, the majority of subjects are male. Racial distribution is similar to the overall population distribution.

  Study phs001515

• Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression

  While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE [Database of Immune Cell Expression, Expression quantitative trait loci (eQTLs) and Epigenomics] project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis.

  Study phs001703

• Chordoma_Sequencing_Project_Whole_Genome

  This is a continuation of the Chordoma Sequencing Project, prelim #G0175-122-CF. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. The Chordoma Foundation will fund the RNA Sequencing/Methylation and SNP6 costs for this project while the whole genome and library sequencing will be covered under the CGP, 2012-2013 core WTSI internal funding. An additional sequencing of three cancer cell lines will be added to this work, financed by the Chordoma Foundation. In this project, the Chordoma foundation will pay for the additional costs of methylation, RNA Seq,

  Study EGAS00001000409

• 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

• Exome data: Histone mutations in human Pre-Leukemic HSC and AML

  Exome sequencing was performed on samples from patients 064, 105, and 8760, including the remission sample for 105. Exomes were captured using the Agilent SureSelect All Exon kit v5 kit and libraries sequenced on HiSeq 2000 or 2500 or 4000.

  Dataset EGAD00001004436

• The South Asia Rheumatic Heart Disease Genetics Network Data

  This dataset comprises over 850 individuals recruited in Uttar Pradesh, India, including cases of rheumatic heart disease based on echocardiographic diagnosis and controls recruited on the basis of normal echocardiograms. For this analysis all available samples were genotyped using the Illumina HumanCore-24 BeadChip platform.

  Dataset EGAD00001004882

• These are from Korean HCC samples with exome sequencing

  Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in 9 genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodelling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (p = 0.016 and p = 0.001, respectively). FGF19 amplifications, known to activate Wnt signalling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (p = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

  Study EGAS00001000604

• BHD-associated kidney cancer

  Background Birt-Hogg-Dub? (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene, FLCN is a tumor suppressor for kidney cancer which plays an important role for energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, how FLCN-deficiency leads to renal tumorigenesis is unclear. Results Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations (CNV) of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. Somatic mutation analysis revealed BHD-associated kidney cancer has quite few common mutations in specific genes; however, chromatin remodeling genes in total were frequently mutated in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis revealed that glycolysis, pentose phosphate pathway and lipid metabolism were upregulated whereas the rate of beta oxydation and TCA cycle is decreased in BHD-associated kidney cancer compared to normal adjacent kidney. Conclusions BHD-associated kidney cancer displays a unique molecular characteristics which is totally different from that of sporadic kidney cancer, providing the mechanistic insight into tumorigenesis under FLCN deficiency as well as the foundation for the development of novel therapeutics for kidney cancer.

  Study JGAS000115

• NINDS-Genome-Wide Genotyping in Parkinson's Disease: First Stage Analysis and Public Release of Data

  Epidemiological studies have estimated a cumulative prevalence of PD of greater than 1 per thousand. When prevalence is limited to senior populations, this proportion increases nearly 10-fold. The estimated genetic risk ratio for PD is approximately 1.7 (70% increased risk for PD if a sibling has PD) for all ages, and increases over 7-fold for those under age 66 years. The role for genes contributing to the risk of PD is therefore significant. This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, 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. Genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls. The NINDS repository was established in 10-2001 towards the goal of developing standardized, broadly useful diagnostic and other clinical data and a collection of DNA and cell line samples to further advances in gene discovery of neurological disorders. All samples, phenotypic, and genotypic data are available to the research community including to academics and industry scientists. In addition, well characterized neurologically normal control subjects are a part of the collection. This collection formed the basis of this first stage study by Fung et al., and the expanded study by Simon-Sanchez et al. The genotyping data was generated and provided by the laboratory of Dr. Andrew Singleton NIA, and Dr. John Hardy NIA (NIH Intramural, funding from NIA and NINDS). 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

  Study phs000089

• Microbiota 16S sequencing study in NSCLC patients eligible for surgery without neoadjuvant treatment

  18 non-small cell lung cancer patients eligible for surgery without neaodjuvant treatment were included in the study at Centre Jean Perrin (France). Patients did not take any antibiotics, food supplements or immunostimulants 2 months prior to inclusion. During surgery, patients underwent partial or complete lobectomy where samples of non-malignant lung tissue, peritumoural tissue and tumour were resected from the removed lobe. This was preceeded by the washing of the removed lobe and obtaining the broncho-alveolar lavage fluid. These four sample types were analysed by 16S sequencing in 17 from 18 patients. The study is a part of the project "Characterization of Microbiota (Intestinal, From Lungs, and Upper Airways) in Patients With Non-small Cell Lung Carcinoma: Exploratory Study " which is registered under ref. NCT03068663 (clinicaltrials.gov).

  Study EGAS00001004728

• NHLBI Family Heart Study (FamHS-Visit1 and FamHS-Visit2)

  The Family Heart Study (FamHS) was funded by the National Heart, Lung, and Blood Institute (NHLBI). It was begun in 1992 with the ascertainment of 1,200 families, half randomly sampled, and half selected because of an excess of coronary heart disease (CHD) or risk factor abnormalities as compared with age- and sex-specific population rates (Higgins et al. 1996). The families, with approximately 6,000 individuals, were sampled on the basis of information on probands from four population-based parent studies: the Framingham Heart Study, the Utah Family Tree Study, and two Atherosclerosis Risk in Communities (ARIC) centers (Minneapolis, and Forsyth County, NC). A broad range of phenotypes were assessed at a clinic examination in broad domains of CHD, atherosclerosis, cardiac and vascular function, inflammation and hemostasis, lipids and lipoproteins, blood pressure, diabetes and insulin resistance, pulmonary function, and anthropometry (FamHS Visit 1). Approximately 8 years later, study participants belonging to the largest pedigrees were invited for a second clinical exam (FamHS Visit 2). A total of 2,756 Caucasian subjects in 508 extended families were examined. A two-phase design was adopted for the genome wide association (GWA) study. In phase-1, 1007 subjects were chosen, equally distributed between the upper and lower quartile of age- and sex-adjusted values for coronary artery calcification, assessed by CT scan in Visit 2. These subjects were chosen to be largely unrelated; 34% of the subjects were from unique families, while 200 other subjects had 1 or more siblings selected into the sample, yielding a sample of 465 unrelated subjects. The remaining family members (N=1749) were genotyped in the phase-2 for replication of the top hits from the phase-1. The results presented here represent those for the analysis of the phase-1 case-control sample for variables assessed in FamHS Visit 1 (from 1992 to 1995) and for the variables assessed in FamHS Visit 2 (from 2002 to 2003). All subjects were typed on the Illumina HumMap 550 chip (Phase 1 genotype). Of these, 33 (3.3%) were excluded due to technical errors, call rates below 98%, and discrepancies between reported sex and sex-diagnostic markers. The final sample of 974 subjects have Visit 2 phenotypes, approximately 100 of these do not have Visit 1 phenotypes. There was no significant plate-to-plate variation in allele frequencies. The covariate adjustments were performed separately by sex using cubic polynomial age and clinical centers, and retaining the terms in the stepwise regression analysis that were significant at the 5% level. Extreme outliers (>4 SD from the mean) were set aside, temporarily, for the adjustments. The final phenotypes were computed for all individuals using the best mean regression models and standardizing to 0 mean and unit variance. The FamHS has contributed GWA results in many phenotype domains (antropometric and adiposity, atherosclerosis and coronary heart disease, lipid profile, diabetes and glicemic traits, metabolic syndrome etc) to meta-analyses and various consortia, including Heard-Costa et al. 2009, Köttgen et al. 2010, Teslovich et al. 2010, Nettleton et al. 2010, Lango et al. 2010, Heid et al. 2010, Speliotes et al. 2010, Dupuis et al. 2010, Kraja et al. 2011.

  Study phs000221

• Whole-genome sequencing of bladder cancers of various stages and grades to search for driver mutations, chromosome-scale somatic changes, mutation signatures and clonal structures.

  This discovery set of tumours cancers with whole-genome sequence data comprised 14 bladder cancers, paired with peripheral blood, that had been collected from unrelated individuals presenting to the Urology Department, Royal Hallamshire Hospital, Sheffield between June 2008 and September 2011. Four cancers were of low-grade papillary morphology (pTaG1-2), five were high grade invading the lamina propria (pT1G3, with two subsequently becoming muscle-invasive); and five were muscle-invasive (pT2-pT3). All tumours were sampled at transurethral resection or cystectomy and had not previously received any other therapy. The presence of a majority of cancer cells in the tumour specimens was confirmed by routine histological assessment. Genomic DNA was extracted from each tumour and paired blood sample using standard methods.

  Study EGAS00001000738

• Harnessing the Electronic Health Record to Predict Risk of Cardiovascular Disease: Sangre Por Salud (SPS) Biobank GWAS Data

  These data are from subjects in the Sangre Por Salud (SPS) Biobank, a Latino population from the Southwest United States. Subjects were genotyped in 2 batches on the Illumina Multi-ethnic Global Array. Data from this study were used for testing a new cardiovascular risk score and evaluating polygenic risk scores. SPS biobank GWAS data is available on 3699 subjects.

  Study phs003553

• Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

  PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

  Study EGAS00001004160

• Development of blood-based biomarkers for precision medicine in castration-resistant prostate cancer

  Cell-free DNA (cfDNA) testing is emerging as a tool for cancer precision medicine. However, little is known about the clinical significance of low-frequency variants detected in circulating cell-free tumor DNA (ctDNA) from castration-resistant prostate cancer (CRPC) patients. We conducted targeted sequencing of cfDNA and paired leukocyte DNA from CRPC patients using molecular barcodes, and ctDNA variants with a variant allele frequency ??? 0.1% were detected using an in-house pipeline.

  Study JGAS000330

• Micro-C sequencing of pediatric BCP ALL

  Micro-C sequencing data of 35 B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) cases were constructed on an Illumina NovaSeq 6000 Sequencing System.

  Dataset EGAD50000001124

• RNA sequencing of pediatric BCP ALL

  RNA sequencing data of 33 B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) cases were constructed on an Illumina nextseq 2000 Sequencing System.

  Dataset EGAD50000001125

• 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

• Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high risk disease

  Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole exome sequencing, copy number variation and/or RNA-Seq for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six chronic phase patients with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15/27 patients (56%) with subsequent BC or poor outcome and in 3/19 optimal responders (16%), P=.007. Frequently mutated genes at diagnosis were ASXL1, IKZF1 and RUNX1. The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia translocation was detected at diagnosis in 11/46 patients (24%) comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9/27 (33%) versus 2/19 optimal responders (11%), P=.07. Thirty-nine patients were tested at BC and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations co-occurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Philadelphia translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.

  Study EGAS00001003071

• Whole Genome Sequencing of INTERVAL (2019-06-12)

  15x Whole Genome Sequencing of 15,000 individuals from the INTERVAL study cohort, phase II. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-06-12.

  Dataset EGAD00001005085

• Alcohol Dependence: Sequencing from Multiplex Families

  Two multiplex for alcohol dependence family studies were initiated based on the gender of a pair of probands. Ascertainment of a pair of AD probands was used to increase the density of alcohol dependence within the family. Identification of male (Cognitive and Personality Factors in Relatives of Alcoholics Family Study) and female (Biological Risk Factors in Female Alcoholics Family Study) alcohol dependent probands was accomplished by identifying an alcohol dependent proband while in treatment in a substance abuse treatment facility in Pittsburgh and surrounding communities who provided contact information for a sibling whom he/she thought might be interested in participating. The studies had identical ascertainment requirements. DNA was banked for all willing participants.

  Study phs001775

• Sequencing data of tumor tissue obtained from GANNET53 study patients

  The GANNET53 clinical trial evaulated novel treatment options for ovarian cancer patients with platinum-resistant relapse. Archival fresh-frozen paraffin embedded tissue was available from 131 of the 133 enrolled patients. NGS sequencing aimed at assessing the mutational spectrum of key ovarian cancer genes (with a focus on TP53), and their relevance for therapy resistance. From available FFPE samples, DNA was extracted and NGS sequenced using the SureSeq™ Ovarian Cancer Panel and the NGS Library Preparation kit covering all exons of 7 key ovarian cancer genes BRCA1, BRCA2,TP53, PTEN, ATM, ATR, NF1 for single nucleotide variants (SNV) and indels. Finally, sequence data from 118 individual FFPE tumor tissue samples were generated.

  Study EGAS50000000935

• Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study

  Study population The WECARE Study is an international multicenter population-based case-control study of cases with asynchronous contralateral breast cancer (CBC) and individually matched controls with unilateral breast cancer (UBC). Recruitment and data collection for the WECARE Study were conducted in two phases, herein referred to as WECARE I (2001–2004) and WECARE II (2009–2012). The study design of the first phase (WECARE I) has been described in detail elsewhere [Bernstein JL, et al 2004, PMID: 15084244]; the second phase (WECARE II) employed a nearly identical approach [Langballe R, et al 2016, PMID: 27400983]. Participants in each phase were identified through eight population-based cancer registries, including six in the United States that contribute to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program: Los Angeles County Cancer Surveillance Program; Cancer Surveillance System of the Fred Hutchinson Cancer Center (Seattle region, WA); State Health Registry of Iowa; Cancer Surveillance Program of Orange County/San Diego-Imperial Organization for Cancer Control (Orange County/San Diego, CA); the Greater Bay Area Cancer Registry (San Francisco Bay Area region and Santa Clara region, CA); and the Sacramento and Sierra Center Registry (Sacramento region, CA). Participants were additionally identified using the Ontario Cancer Registry (Canada) and the Danish Breast Cancer Cooperative Group Registry, supplemented by data from the Danish Cancer Registry. The study protocol was approved by the institutional review or regulatory ethics boards at each study site. Data collection Study participants were interviewed by telephone using a structured questionnaire aimed at evaluating known or suspected breast cancer risk factors, including personal demographics, medical history, menstrual and reproductive history, family history of cancer, use of hormones, smoking, and alcohol intake. Risk factor status was assessed during the period prior to first diagnosis, as well as between first diagnosis and reference date (i.e., the at-risk period for CBC). Detailed data on treatment and tumor characteristics were obtained directly from cancer registry records or by abstracting medical records, including pathology and surgical reports, radiation oncology clinic notes, and systemic adjuvant treatment data. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Biospecimens were collected from study participants for genotyping: blood collected from WECARE I women; and saliva collected from WECARE II women.

  Study phs003945

• Kids First: Whole Genome Sequencing in Structural Defects of the Neural Tube

  Myelomeningocele (aka meningomyelocele, MM) is the most severe form of spina bifida, a neural tube defect (NTD) in humans and the most common CNS birth defect. MM is considered a genetically complex disease, and occurs in 3.72/10,000 live US birth, and is partly preventable with prenatal folate, but the genetic basis and the mechanisms by which folate work to reduce disease incidence remain obscure. MM is associated nearly uniformly with prenatal hydrocephalus and the Arnold-Chiari malformation, as well as paraplegia and lifelong neuromotor disability. The genes for several rare syndromic forms of NTDs are known, but the causes for the majority with sporadic MM remain unknown. Despite the importance of MM, most previous research has been limited to targeted sequencing and association studies of folate metabolism genes, or very small-scale exome sequencing. We hypothesize that de novo mutations (DNMs) produce likely gene disrupting (LGD) events that contribution to MM risk. Using conservative estimates of between 50-100 recurrently mutated discoverable genes contributing to risk, and our preliminary data demonstrating an excess of LGD DNMs in MM compared with control individuals, we estimate that with a cohort size of 1000 trios, we should uncover between 5-20 new recurrently mutated genes underlying MM, with minimal false-discovery. With this in mind, we formed the Spina Bifida Sequencing Consortium, and established a platform for data and sample sharing. Preliminary analysis of our first batch of 100 trios analyzed by WGS from GMKF suggests a wealth of important gene mutations. We have embarked on a new recruitment effort of an additional cohort of 400 new simplex MM trios, in collaboration with the US Spina Bifida Association, consented trios to allow for data sharing, and have performed detailed sample quality control. We also have preliminary data that use of dried bloodspot DNA from trios performs comparably to whole blood DNA, so will be happy to swap saliva for bloodspot recruitment at NIH's preference. This cohort is now half-way assembled, with the remaining cohort to be ascertained in the next 6 months. We have established a workflow for de novo SNP/INDEL/SV detection from WGS and have ample computer storage and nodes to see the project to completion. We also plan to continue recruitment into the future with the goal of 2000 trios in the next 5 years. We propose a detailed bioinformatics workflow to identify gene mutations within a statistical framework, considering detailed scRNA expression profiling from developing mammalian neural tube, and have developed a robust functional validation workflow using Xenopus and mouse gene targeting. Our project has the potential to uncover a host of causes for this most common of the CNS birth defects, paving the way for future breakthroughs in detection, treatment, and prevention.

  Study phs002591

• Molecular characterization of NASH-HCC

  We collected 80 NASH-HCCs formalin fixed paraffin-embedded (FFPE) samples from 5 different institutions. NASH was diagnosed in FFPE samples by at least two expert pathologists following a described histological algorithm (Bedossa et al., Hepatology, 2012). All NASH patients included in the study were HBV- and HCV-negative. Patients reporting alcohol consumption ≥ 20 g/day for women and 30 g/day for men, as well as patients with a known liver disease superimposed to NASH were excluded. Tumour and paired non-tumour gDNA of NASH-HCC FFPE samples was submitted to Whole Exome Sequencing (WES). Exome capture and sequencing library preparation were performed using the SureSelect Human All Exon V5, no UTR hybridization capture kit from Agilent (Target Size 50 Mb). Libraries were sequenced on an Illumina HiSeq 4000 instrument with 100-bp paired-end reads.

  Dataset EGAD00001007524

• Y-phylogeny-haplogroupDE (2019-04-03)

  High-coverage whole genome sequences using Hiseq X for 4 individuals to investigate their Y chrosmosmes' relationship to the known phylogeny. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004892

• Isotype-resolved sequencing of B-cell receptor in sorted memory populations (2017-09-13)

  Optimisation of ex vivo Memory B cell Expansion/Differentiation for Interrogation of Rare Peripheral Memory B Cell Subset Responses 1) 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/ This dataset contains all the data available for this study on 2017-09-13.

  Dataset EGAD00001003747

• Myocardial Infarction Genetics Exome Sequencing Consortium: Pakistan Risk Of Myocardial Infarction Study

  The Pakistan Risk of Myocardial Infarction (PROMIS) study is a retrospective multicenter case-control cohort study of individuals with and without coronary heart disease from Pakistan. Multiple biological samples have been collected from the participants including DNA, plasma, serum, and whole blood. The goal of the study is to recruit 20,000 cases and 20,000 controls of Pakistani descent. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using either Agilent's SureSelect Human All Exon Kit v2 or Illumina's ICE capture reagent; and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000917

• Integrative Analysis for Multi-Omics Data in Non-Small-Cell Lung Cancer

  We conducted epigenetic and transcriptomic mapping of primary non-small cell lung tumors and non-neoplastic tissues. 20 non-neoplastic lung tissues and 18 non-small cell lung tumors were obtained from Biorepository and Tissue Technology Shared Resource at Moores Cancer Center, UC San Diego. All tumor samples were in pathological stages I and II. 8 pairs of samples were "matched", meaning that the tumor and normal tissues came from the same patient. Microfluidic oscillatory washing–based chromatin immunoprecipitation followed by sequencing (MOWChIP-seq) was used to profile the binding of H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3. SmartSeq-2 was used to map mRNA expression. We identified a large number of differentially modified regions for both epigenetic and transcriptomic markers between tumors and normal tissues. Deep learning model showed extensive transcription factor network rewiring. Raw sequencing data of the ChIP-seq and RNA-seq libraries are available through this dbGaP submission.

  Study phs003113

• VitGene Generalized Vitiligo Genetics Study-Phase 2

  Generalized vitiligo is an autoimmune disease in which melanocyte loss results in patchy depigmentation of skin and hair. For this third GWAS of generalized vitiligo, SNPs were genotyped in 1,059 generalized vitiligo cases of European-derived white (EUR) ancestry using the Illumina Human OmniExpress BeadChip array. The data were combined with those of Phase 1 and Phase 2 to provide at least 85% power to detect associations with OR > 1.22 at genome-wide significance (P = 5 x 10-8) for MAF > 0.25.

  Study phs000224

• NHLBI TOPMed: Pulmonary Fibrosis Whole Genome Sequencing

  This is a set of cases diagnosed with idiopathic pulmonary fibrosis, a fatal interstitial lung disease. These cases were included in the TOPMed phase three studies. The planned study will compare these cases to within-TOPMed controls for genome-wide association studies.

  Study phs001607

• Dataset of 10 WES from bladders tumors and PBMC of 4 non-muscle invasive bladder cancer patients

  WES (FASTQ files) of paired tumor and PBMC samples of non-muscle-invasive bladder cancer patients. All CTRL samples originate from PBMC. For patient UC2, DNA from 3 different synchronous tumors were extracted. DNA from tumors was extracted from fresh frozen tumors,except for patient UC4 (FFPE). NB : patients aliases are the following :ROXY : UC1, OMAD : UC2, MAKI : UC3, HAPE : UC4

  Dataset EGAD50000002008

• Warfarin Pharmacogenetics: Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)

  Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

  Study phs000708

• Integrated clinical, whole genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

  We report the first combined analysis of whole genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole genome and transcriptome sequence was obtained from 9 anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 years prior to death. Transcriptome analysis revealed increased expression of AR-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only 1 of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today given this knowledge, use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations is critical for actionability, and can only be determined through analysis of multiple sites of metastasis. Our findings suggest that a large set of deeply analyzed cases could serve as powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.

  Dataset EGAD00001001869

• Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Pancreatic Lesions

  The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. We found that neoplastic lesions occur frequently in healthy organs, in donors as young as in their 3rd decade of life. Using the 10X Genomics Platform, we performed single cell RNA sequencing on 7 donor pancreata, 6 of which we separately sequenced tissue from the pancreas head and tail, for a total of 11 sequencing runs. Of note, because one of our runs (containing sequencing from pancreas head and tail) did not pass qc, our final analysis in our study utilized 6 donor pancreata, 5 of which contained pancreas head and tail sequenced separately. This is a robust single-cell dataset of healthy, nonpathologic pancreas tissue and includes acinar, ductal, and non-epithelial cells (myeloid cells, fibroblasts, endothelial cells, lymphocytes).Briefly, the donor pancreas was dissected by a clinically-trained pancreatobiliary surgeon. The organ was dissected into head, body, and tail, with portions of each placed into DMEM media with 1% BSA/10µM Y27632. Tissue was minced into 1mm3 pieces, then digested with 1 mg/mL collagenase P for 20-30 min at 37°C with gentle agitation. Digested tissue was rinsed three times with DMEM/1% BSA/10µM Y27632, then filtered through a 40µm mesh. Resulting cells were submitted to the University of Michigan Advanced Genomics Core for single cell sequencing using the 10x Genomics Platform. FASTQ files of all sequencing runs along with clinical annotation of donors is available through this dbGaP submission.

  Study phs003229

• Ischemic stroke in a Swedish case-control study.

  Background. Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS, based on 29 SNPs discovered by genome-wide association studies (GWAS) and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other “traditional risk factors”, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Methods and results. Twenty-nine SNPs were genotyped in 3,677 stroke cases and 2,415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the entire material, and separately for the three samples. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the entire material [OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS p=0.003] with similar trends in all three samples; LSR [1.050 (0.967-1.140)]; p=0.25], MDC [1.168 (1.060-1.288); p=0.002] and SAHLSIS [1.124 (0.997-1.267); P=0.055]. Measures of discrimination and reclassification improved marginally using the GRS. Conclusions. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.

  Study EGAS00001000936

• International Consortium for Blood Pressure (ICBP)

  The ICBP consortium is an international effort to investigate blood-pressure genetics. The consortium was formed by two parent consortia, the CHARGE-BP consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology - blood pressure) and the GBPGEN consortium (Global Blood Pressure Genetics Consortium). In 2011 we performed genome-wide association analyses based on genome-wide SNPs imputed to HapMap for systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure and pulse pressure (MAP and PP). In 2016 we performed an analysis based on the Cardio-MetaboChip for SBP and DBP. All these datasets are available here, however, full association statistics including effect size directions, only under controlled access by dbGaP.

  Study phs000585

• Transcriptional and functional profiling defines human small intestinal macrophage subsets

  Macrophages (Mf) are instrumental in maintaining immune homeostasis in the intestine, yet studies on origin and heterogeneity of human intestinal Mf are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMo), were largely replaced within 3 weeks, whereas two subsets with features of mature Mf, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptomic analysis showed that all Mf subpopulations subsets were markedly distinct from PBMo and dendritic cells (DC). Compared to PBMo, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli, but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMo.

  Study EGAS00001002093

• Assessment of Health-related Quality of Life in Rare Kidney Stones

  The purpose of this study is to learn about Health-related Quality Of Life (HRQoL) in patients enrolled in the Rare Kidney Stone Consortium (RKSC) registries. Quality of life studies look at different aspects of both physical and mental components of people's lives. HRQoL data for people affected by kidney stones are not currently available for people followed over time. All participants enrolled in the RKSC registries will be invited, via email or postal mail, to participate in this study. Health-related quality of life in people with rare kidney stones enrolled in the RKSC registries will be measured. Instruments used in this study are the SF-10 for pediatric participants and SF-36v2 for adult participants. The surveys will be completed online. Participants without a computer or internet access will participate using a paper version of the survey. These surveys will be done at enrollment and annually thereafter. The SF-36v2 includes 36 questions and is estimated to take 15 minutes for its completion, while the SF-10 includes 10 questions and could be completed in 5 minutes. The research questions are: Assessment of HRQoL in patients with rare kidney stones. Comparison of HRQoL results between rare kidney stone formers, general population and other populations with relevant chronic diseases. Comparison of HRQoL results in the same populations affected by different stones and analyzed with attention to the effects of various factors included in the disease registry, such as stone activity, burden of urologic interventions, medication and other treatments. Evaluation of HRQoL and its trends over time in patients undergoing treatment for rare kidney stones. About this study: The plan is to have 400 participants from all four registries take part in this multi-center study. The assessment of your HRQoL will be done annually for 5 years.

  Study phs001770

• ctDNA monitoring using patient-specific sequencing and integration of variant reads - Lung cohort

  Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to individual parts per million. This resulted in median Area Under the Curve (AUC) values of 0.98 in advanced cancers, and 0.80 in early stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that the INVAR may be applied without requiring personalized sequencing panels, so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

  Study EGAS00001004447

• ctDNA monitoring using patient-specific sequencing and integration of variant reads - Breast cohort

  Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to individual parts per million. This resulted in median Area Under the Curve (AUC) values of 0.98 in advanced cancers, and 0.80 in early stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that the INVAR may be applied without requiring personalized sequencing panels, so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

  Study EGAS00001004446

• Somatic IL4R Hotspot Mutations in Primary Mediastinal Large B-cell lymphoma lead to constitutive JAK-STAT activation

  Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 out of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8 leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain-of-function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.

  Study EGAS00001002796

• An_evaluation_of_different_strategies_for_large_scale_pooled_sequencing_study_design_

  Second generation sequencing technology has enabled the design of large-scale sequencing experiments in targeted disease-related regions in thousands of cases and controls. Cost implications dictate a pooled DNA sequencing design, evaluation of allele frequency differences based on the resequenced samples and large-scale targeted follow-up in further samples. To evaluate the feasibility of this approach and to assess different study design strategies, we have carried out a pilot study which tests the feasibility of PCR-based and pull-down DNA pooling for (a) SNP discovery and (b) allele frequency comparison purposes. All samples are from the HapMap or 1958 BC. The sample composition of the pool is listed below: Pool 5: 31 HapMap Individuals (NA12249, NA12156, NA12004, NA11831, NA12716, NA11832, NA11993, NA12057, NA11995, NA12006, NA12144, NA12802, NA12146, NA12005, NA12003, NA07000, NA12043, NA12044, NA11992, NA11881, NA11994, NA07345, NA12154, NA06994, NA06985, NA12239, NA07022, NA07034, NA12155, NA07056, NA06993); 19 1958 BC Individuals (WTCCC88214, WTCCC88215, WTCCC88216, WTCCC88217, WTCCC88222, WTCCC88233, WTCCC88240, WTCCC88241, WTCCC88242, WTCCC88247, WTCCC88249, WTCCC88262, WTCCC88264, WTCCC88278, WTCCC88294, WTCCC88298, WTCCC88302, WTCCC88305, WTCCC88321) Some pools were carried out in duplicate to assess reproducibility. We focused on 10 (PD), 7(PCR) chromosomal regions, ~2(PD), ~1.6 (PCR) Mb in total.

  Study EGAS00001000134

• Genome-wide DNA Methylation is Predictive of Outcome in Juvenile Myelomonocytic Leukemia

  Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in this disease vary dramatically from spontaneous resolution with little or no treatment to rapid relapse after hematopoietic stem cell transplantation. Given the high morbidity and late effects of transplant, it is critical to identify patients at diagnosis who can be observed rather than transplanted. We hypothesized that assessing DNA methylation status would help predict disease outcome. Genome-wide DNA methylation profiling using the Illumina 450k platform in a discovery cohort of 39 patients was performed. Unsupervised hierarchical clustering based on the most highly variable CpG sites identified three clusters of patients. Importantly, these clusters differed significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Of particular interest is that all but one of fourteen patients experiencing spontaneous resolution of their disease clustered together and closer to 22 healthy controls than the other JMML cases. This study demonstrates that DNA methylation patterns in JMML are predictive of outcome in this heterogeneously behaving disease and can identify patients who are most likely to experience spontaneous resolution.

  Study EGAS00001002700

• MGP Panel: a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

  We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies.

  Study EGAS00001006222

• Sequencing data for Maturity-Onset Diabetes of the Young (MODY) patients in south India

  We performed whole genome, whole or targeted exome sequencing for 289 individuals from India. This included 152 clinically diagnosed MODY and 137 control samples. Whole genome libraries were constructed using TruSeqNano DNA Library Preparation Kit (Illumina, CA) and sequenced on Illumina HiSeq2500 (Illumina, CA). The whole exome analysis was performed using Agilent SureSelect (Santa Clara, CA) Human All Exome kit v5 (50 Mb). Exome capture libraries were sequenced on HiSeq 2500 (Illumina, CA). Targeted exome sequencing was performed using custom probes corresponding to 1965 genes implicated in pancreatic cell biology and/or diabetes.

  Dataset EGAD00001003919

• National Sleep Research Resource (NSRR): Cleveland Family Study (CFS)

  The Cleveland Family Study (CFS) is a family-based study of sleep apnea, consisting of 2,284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study began in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. National Institutes of Health (NIH) renewals provided expansion of the original cohort, including increased minority recruitment, and longitudinal follow-up, with the last exam occurring in February 2006. The CFS was designed to provide fundamental epidemiological data on risk factors for sleep disordered breathing (SDB). The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first-degree relatives, spouses and available second-degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first-degree relatives. Each exam, occurring at approximately 4-year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. Currently, data of 710 individuals are available for use through BioData Catalyst (with genotype data available through dbGaP).The National Sleep Research Resource (NSRR) is a NIH-supported sleep data repository that offers free access to large collections of de-identified physiological signals and related clinical data from a large range of cohort studies, clinical trials and other data sources from children and adults, including healthy individuals from the community and individuals with known sleep or other health disorders. The goals of NSRR are to facilitate rigorous research that requires access to large or more diverse data sets, including raw physiological signals, to promote a better understanding of risk factors for sleep and circadian disorders and/or the impact of sleep disturbances on health-related outcomes. Data from over 15 data sources and more than 40,000 individual sleep studies, many linked to dozens if not hundreds of clinical data elements, are available (as of Feb. 2022). Query tools are available to identify variables of interest, and their meta-data and provenance.

  Study phs002715

• UK Biobank whole cohort directly genotyped and imputed data (~500,000 participants)

  Genotype data is available for all 500,000 participants in the UK Biobank cohort. Genotyping has been performed using the Affymetrix UK BiLEVE Axiom array on an initial 50,000 participants and the remaining 450,000 participants have been genotyped using the Affymetrix UK Biobank Axiom® array. The two arrays are extremely similar (with over 95% common content).Quality control and imputation (to over 90 million SNPs, indels and large structural variants) has been performed by a collaborative group headed by the Wellcome Trust Centre for Human Genetics.The following data are available:* A clean set of QC’ed genotype calls* Confidence values that a genotype call is correct* Intensity data to generate cluster plots* Extensive QC information regarding SNPs and samples including SNP metrics, batch effects, population structure and relatedness* Imputed dataFor further information, please refer to the UK Biobank website

  Study EGAS00001002399

• H3K27ac ChIP-seq in primary inflammatory macrophages from 2 minor allele homozygotes and 2 major allele homozygotes at rs2836882

  This dataset consists of H3K27ac ChIP-sequencing in inflammatory (TPP) macrophages from 2 minor allele homozygotes and 2 major allele homozygotes at rs2836882. Monocytes were positively selected from PBMC using CD14 Microbeads and inflammatory macrophage differentiation performed using conditions that model chronic inflammation (TPP): 3 days GM-CSF (50ng/mL) followed by 3 days GM-CSF, TNFa (50ng/mL), PGE2 (1mg/mL), and Pam3CSK4 (1mg/mL). After harvesting, cells were cross-linked, quenched, lysed, and sheared. Immunoprecipitation of histone-DNA complexes was performed overnight at 4C with rotation using an anti-H3K27ac antibody and the SimpleChIP Plus Sonication ChIP kit (Cell Signaling Technology). Following reverse cross-linking, 50ng of immunoprecipitated DNA or input DNA were used to prepare sequencing libraries using the iDeal Library Preparation kit (Diagenode), according to manufacturer instructions. 10 PCR cycles were used for the amplification step and size selection was not performed. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 (Agilent) and the libraries were sequenced in pools of 8, with each pool being sequenced in 2 lanes of an Illumina HiSeq2500 high output flow-cell (50bp, single-end reads). Raw data are provided as raw and aligned single-end sequencing reads from H3K27ac-bound DNA and the input chromatin. Raw reads were trimmed using Trim Galore and aligned to the reference human genome (hg19) using Burrows-Wheeler Aligner (v0.7.12) with default parameters. Aligned reads were converted to BAM files, sorted, and technical duplicates merged before indexing – all using SAMtools (v1.4). PCR duplicates were identified using Picard tools (v2.18.1) and removed together with unmapped reads using SAMtools (v1.4). The resulting BAM files were re-sorted and indexed after filtering.

  Dataset EGAD00001011351

• scRNA seq and scTCR seq data from 5 melanoma patients

  The Chromium Controller and Chromium X platfor of 10X Genomics were used for single cell partitioning and barcoding. Each cell's transcriptome was barcoded during reverse transcription, pooled cDNA was amplified and Single Cell 5' Gene Expression (GEX), V(D)J and Feature Barcode (FB) Libraries were prepared according to the manufacturer's protocols (CG000330 and CG000331, 10X Genomics). All libraries were quantified and normalized on library QC data generated on the Bioanalyzer system according to manufacturer's protocols (G2938-90321 and G2938-90024, Agilent Technologies). Based on the expected target cell counts, a balanced library sub-pool of samples was compsed for SC5'GEX, V(D)J and FB libraries. Library sub-pools were quantified by qPCR, accodring to the KAPA Library Quantification Kit Illumina(R) Platforms protocol (KR0405, KAPA Biosystems). Based on qPCR results a final sequencing pool was composed. Paired end sequencing was performed on a NovaSeq 6000 Instrument (Illumina) using NovaSeq 6000 Reagent Kits v1.5 100 cycles (cat. no. 20028401, 20028319, 20028316 Illumina), using 28 cycles for Read 1, 10 cycles for Read i7, 10 cycles for Read i5 and 90 cycles for Read 2.

  Dataset EGAD50000001155

• RNA sequencing of CAR-T cells with CD38-CD73-Tim-3-HLA-DR+ phenotype and others in infusion products of tisagenlecleucel for B-cell precursor acute lymphoblastic leukemia

  We enrolled 19 patients with BCP-ALL who took tisagenlecleucel, and infusion products and patient samples were obtained before and after CAR-T infusion. Single-cell analysis by CyTOF revealed that central memory CAR+ T cells increased in long-term responders, whereas PD-1highCD38highCXCR3+ effector CAR+ T cells were enriched in relapsed patients after CAR-T infusion. Furthermore, in long-term responders, CAR+ T cells obtained from infusion products were enriched with CD38-CD73-Tim-3-HLA-DR+ phenotype, and characterized by decreased ability to produce adenosine, and they showed more memory-like transcriptomic characteristics. We elucidated the characteristics of tisagenlecleucel related to a durable response, which could contribute to improving the clinical outcome.

  Study JGAS000760

• Bulk RNA and ATACseq of 2 XLP patients and 5-6 HD

  The dataset contains five samples from P1, one pre-HSCT and four post-HSCT, one sample from P2 and 5-6 HD. RNAseq reads were processed using the LUMC BIOWDL RNAseq pipeline v5.0.0 (https://github.com/biowdl/RNA-seq). Genes with log2CPM≥1 in at least 10% of all samples were retained for downstream analysis. Differential gene expression analysis was performed using the dgeAnalysis R-Shiny application (https://github.com/LUMC/dgeAnalysis/tree/v1.4.4). ATACseq reads were processed using the LUMC BIOWDL Chipseq pipeline 1.0.0-dev (https://github.com/biowdl/ChIP-seq).

  Dataset EGAD50000002072

• ovarian cancer sample RNA-seq

  Tissue samples were collected from 18 ovarian cancer patients. After mechanical and enzymatic dissociation, a part of these tissues underwent growth factoromics analysis. For four cases, single-cell sequencing analysis was conducted under conditions with or without estradiol. Additionally, the remains of the tissues were frozen and subsequently subjected to bulk RNA-sequencing on 17 of these samples. Sixteen cases were diagnosed as HGSOC, while two samples were clear cell or mucinous type (Extended Data Table 1). All cases were grade 3, and none had received neoadjuvant chemotherapy. - Group C1, Epithelial Ovarian Cancer(EOC) patients with estrogen responsiveness : 6 samples - Group C2, Epithelial Ovarian Cancer(EOC) patients with estrogen non-responsiveness : 10 samples - non-classified 1-sample

  Dataset EGAD50000000613

• Deciphering the genomic, epigenomic and transcriptomic landscapes of pre-invasive lung cancer lesions to determine prognosis

  Background: Lung carcinoma-in-situ (CIS) lesions are the pre-invasive precursor to lung squamous cell carcinoma. However, only half progress to invasive cancer in three years, while a third spontaneously regress. Whether modern molecular profiling techniques can identify those pre-invasive lesions that will subsequently progress and distinguish them from those that will regress is unknown. Methods: Progressive and regressive CIS lesions were laser-captured and their genome, epigenome and transcriptome interrogated. We analysed 83 progressive lesions, 41 regressive and 33 normal epithelial control samples. DNA methylation and gene expression profiles were further validated using publicly available lung cancer data. Results: Somatic mutation burden was higher in progressive lesions than regressive CIS lesions, across base substitutions, rearrangements, and copy number changes. Driver mutations were present in both progressive and regressive CIS lesions, but were more numerous in progressive cases. Progressive and regressive CIS lesions had distinct epigenomic and transcriptional profiles, with a strong chromosomal instability signature. Gene expression, methylation and copy number profiles can all predict accurately which CIS lesions will progress to lung cancer. Conclusion: Pre-invasive CIS lesions that will subsequently progress to invasive lung cancer can be distinguished from those that will regress using molecular profiling. Progression is associated with a strong chromosomal instability signature. These findings inform the development of novel therapeutic targets.

  Dataset EGAD00001003883

• RNA sequencing

  For RNA sequencing: All sample numbers starting with 6717 are tumor samples which has been sequenced using transcriptomics (see BAM files). It concerns biopsies of metastatic lesions from patients with BRAFV600 mutated melanoma, obtained before, during and after the study treatment (see samples metadata). RNA sequencing is performed using the Illumina Novaseq 6000 system.

  Dataset EGAD50000000383

• SG10K_Pilot Dataset: Whole genome sequencing data of 4810 individuals from Singapore

  Genomic data obtained from the joint processing and variant calling of 4,810 individuals from Singapore. VCF files are by Chromosome (chr. 1-22 plus X) for all 4,810 individuals. Self-reported ethnicity is found in the "Region" column of metadata file.

  Dataset EGAD00001005337

• A new beta-globin mutation responsible of a beta-thalassemia (HbVar database ID 2928) was observed in 8 unrelated French families. The mutation carriers originated from Nord-Pas-de-Calais, a Northern French region where the chief town is Lille.5 unrelated mutation carriers were genotyped for a set of 12 microsatellites from chromosome 11, around the beta-globin gene. Among the 5 mutation carriers, 4 were genotyped for 97 European Ancestry Informative SNPs (EAIMs). 32 controls from Nord-Pas-de-Calais were genotyped for the microsatellites and SNPs.

  Dac EGAC00001000245

• Heart Failure Network: Functional Impact of GLP-1 for Heart Failure Treatment (HFN FIGHT-BioLINCC)

  Objectives To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. Background Heart failure was the leading cause of hospitalization in the United States with more than 4 million admissions per year from 2003–2009. Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). As heart failure progresses, these abnormalities become more pronounced and are observed in both patients with and without type 2 diabetes. At this time of this study, there was no heart failure therapy that targeted these metabolic abnormalities; however, in earlier clinical studies, glucagon-like peptide 1 (GLP-1) agonists showed cardioprotective effects in patients with advanced heart failure, irrespective of type 2 diabetes status. Glucagon-like peptide 1 is an endogenous incretin hormone that improves insulin sensitivity with minimal risk of hypoglycemia. This study was created to determine if use of GLP-1 agonists improved clinical stability in recently hospitalized patients with acute heart failure and reduced LVEF. Participants There were 300 participants. Design Participants were identified by hospital admission records and were enrolled during either the last 24 hours of his or her hospitalization for heart failure or the 2-week interval after the hospitalization. Baseline evaluations were conducted, which included echocardiographic measures, the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire (KCCQ), and blood tests. After the baseline evaluation, patients were randomized in a 1:1 ratio to receive either the GLP-1 agonist liraglutide or placebo as a daily subcutaneous injection. The protocol involved titration of study drug dosage as tolerated every 14 days from 0.6 mg/d to 1.2 mg/d to 1.8 mg/d during the first 30 days of the trial (as tolerated). Follow-up testing was performed at 30-, 90-, and 180-day study visits. The primary end point was a global rank score in which all participants, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level from baseline to 180 days. Conclusions The GLP-1 agonist liraglutide did not improve post-hospitalization clinical stability in patients with advanced heart failure and reduced LVEF. There was no significant between-group difference in the global rank scores and furthermore, there were no significant differences detected in any of the secondary endpoints.

  Study phs003542

• Kids First: Genomics of Orofacial Cleft Birth Defects in Latin American Families

  The Gabriella Miller Kids First Pediatric Research Program) (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and https://kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft (OFC) birth defects in Latin American families is a whole genome sequencing study of 283 Latin-American parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, and including a collaboration with Dr. Lina Moreno Uribe and Dr. Andrew Lidral of the University of Iowa. All families were ascertained through the Clinica Noel where patients with OFCs receive care from the Antioquia University School of Dentistry in Medellin, Colombia (key on-site colleagues included Dr. Luz Consuelo Valencia-Ramirez and Dr. Mauricio Arcos-Burgos). Genetic studies have shown that this population is comprised of an admixture of immigrant male Caucasians (mainly Spaniards and Basques) and native Amerindian females. Every subject has had a genetic evaluation, including a pedigree analysis for a family history of clefting and other birth defects, a pregnancy history for environmental exposures, and a complete physical exam to rule out suspected or known syndromes or environmental phenocopies. Sequencing was done by the Broad Institute sequencing center funded by the Kids First program (grant number U24-HD090743). The case in each of the Kids First OFC trios has cleft lip (CL, Figure A below), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is identify specific OFC risk variants in Latin American families by performing whole genome sequencing of parent-case trios.

  Study phs001420

• Genome-Wide Scan for Genetic Variants Associated with Early-Onset Prostate Cancer

  This is a genome-wide association scan of 931 early-onset prostate cancer cases of European ancestry. The samples were selected from prostate cancer studies at the University of Michigan. Controls were previously genotyped individuals selected from the Cancer Genetics Markers of Susceptibility (CGEMS) and Illumina's iControlDB database.

  Study phs001185

• A Perioperative Study of Safusidenib in Patients with IDH1-Mutated Glioma

  10 participants with a radiological or pathological diagnosis of WHO Grade 2 lower-grade glioma (LGG) were recruited at a single center starting in December, 2022. Eligibility criteria permitted participants who had undergone prior surgery for WHO Grade 2 LGG, but excluded those with a history of prior radiation or chemotherapy.In Part A of the study, participants underwent an initial craniotomy with tumor biopsy and a lumbar puncture for cerebrospinal fluid (CSF) collection at study entry. Following sample collection, participants received safusidenib at the recommended phase 2 doses of 250 mg twice daily (b.i.d.) for a period of 22–36 days. This was followed by a second craniotomy for maximal safe tumor resection and a repeat lumbar puncture within 5 hours of the final pre-resection dose of safusidenib. Tumor, blood, and CSF samples were collected at both surgical time points for comprehensive translational research.Molecular analyses were performed on samples collected at both time points. These included pharmacokinetics (PK), targeted metabolomics, whole-genome sequencing (WGS) of tumor tissue, single-nucleus RNA sequencing (snRNA-seq), and DNA methylation profiling on all patients. Targeted metabolomics was conducted on samples from 9 participants, while spatial transcriptomics and spatial metabolomics were performed on tumor tissue from 3 participants each. Histone methylation profiling was conducted on samples from 8 participants.

  Study phs003976

• Cell line data (RNAseq, ATACseq, ChIPseq)

  Content: 2 GB RTK I cell lines (LN229, ZH487) in two conditions (NT control and shSOX10). RNAseq: single replicates per condition, polyA+ RNA sequencing, SE. ATACseq: biological replicates per condition, SE. ChIPseq (histone H3 modifications, LN229 only): all marks for each condition were pooled and sequenced on two lanes for each pool. ChIPseq (BRD4 and SOX10): SOX10 libraries were sequenced on single lanes. BRD4 samples were multiplexed and sequenced in two lanes. ChIPseq input samples are also included. Data type and technology: RNAseq: SE 50bp sequenced on HiSeq2000/4000. ATACseq: SE 50bp sequenced on HiSeq2000/4000. ChIPseq: SE 50bp sequenced on HiSeq2000/4000.

  Dataset EGAD00001005493

• POPCOL: population-based colonoscopy.

  PopCol is a cohort study in Stockholm, Sweden that includes a data-rich set of individuals with data available from bowel symptoms questionnaires, gastroenterology visits and biospecimens (genotype and 16S sequencing from blood and stool samples, respectively). Genotyping was carried out using the Illumina HumanOmniExpressExome-8v1 arrays at the SciLifeLab NGI facility in Uppsala, Sweden. Fecal DNA was extracted from samples kept at -80°C using Qiagen 5 QIAamp DNA Stool Mini Kits and analyzed using 16S rRNA gene amplicon sequencing (in the V1-V2 hypervariable region). This was performed on the Illumina MiSeq platform at the Institute of Clinical Molecular Biology (IKMB) in Kiel, Germany. Of these, six PopCol participants were PPI users and 12 used antibiotics. The study was approved by the local Committee of Research Ethics (Forskningskommitté Syd) at Karolinska Institutet, Stockholm, in November 2001. Written informed consent was obtained from all participants

  Study EGAS00001004869

• Spatiotemporal Transcriptome of the Human Brain

  Comprehensive knowledge about the spatiotemporal dynamics of the brain transcriptome is essential for a better understanding of neurodevelopment, sexual dimorphism, and evolution, as well as our increased susceptibility to certain brain disorders. We generated and analyzed genome-wide exon-level transcriptome data from 16 brain regions of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genome-wide genotyping of 2.5 million SNPs and assessed genome normality for all donors. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment.

  Study phs000406

• ADAGESIII: Contribution of genotype to glaucoma phenotype in African Americans

  Glaucoma results in vision loss due to damage of the optic nerve that is irreversible if undetected or untreated. The most common form of glaucoma is primary open angle glaucoma (POAG). While glaucoma affects all races, persons of African descent are disproportionately affected; studies show African-Americans (AAs) are about four to five times more likely than Caucasian Americans to develop the disease. Glaucoma is the leading cause of irreversible blindness in Americans of African descent, and the second leading cause in all Americans. The lack of understanding about the etiology of POAG impedes our ability to identify and treat it early in its development. Evidence of genetic contribution in the pathogenesis of POAG is well established. Since POAG tends to run in families, it is critical to identify the genetic basis of the disease in order to develop effective therapies for early intervention. While genome wide association studies (GWAS) for glaucoma have been completed for Caucasian populations, evidence from other studies suggests that a GWAS of glaucoma specific genes to the African-American population will yield unique and important findings for both this population and for glaucoma in general. A better understanding of the relationship among the stage of disease, the rate of change, ancestry, and other important risk factors being tracked in the ongoing African Descent and Glaucoma Study (ADAGES) will allow us to evaluate the relationship between genetics, visual loss and structural damage in this high-risk cohort. The scientific plan for this new study focuses on glaucoma in ∼2058 African-Americans by detailed phenotyping of new subjects, acquisition of samples from both new and established previously phenotyped study subjects for a repository, establishment of a data coordinating center, and genome wide association studies. The recruitment, enrollment, and phenotyping of both established and new subjects occurs at five clinical centers, University of California (UCSD), New York Eye and Ear Infirmary (Mt Sinai) and Columbia University Medical Center, a private practice in the Atlanta area, the University of Alabama at Birmingham, and the Robert Cizik Eye Clinic in Houston, TX. UCSD is also the location for the Data Coordinating Center and the Repository with Robert N. Weinreb as Principal Investigator. LA BioMed at Harbor-UCLA did the genotyping with a GWAS panel of ∼1 million single nucleotide polymorphisms (SNPs) using the Illumina MEGA array under the direction of Jerome Rotter, Ida Chen, and Kent Taylor.

  Study phs001673

• Exome-sequencing of H3-K27M glioma.

  Fastq or bam files are deposited for 28 patient H3-K27M diffuse midline gliomas. UMPEDD65 was profiled by targeted exome-sequencing using the TSO500 Illumina assay, while all other samples were sequenced by whole-exome sequencing.

  Dataset EGAD00001009269

• A non-canonical lymphoblast in refractory childhood T-cell leukaemia

  Refractory cancers may arise either through the acquisition of resistance mechanisms by cancer cells or represent distinct diseases. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we performed single cell mRNA sequencing of T-ALL from children who did or did not respond to initial treatment. We identified a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease.

  Study EGAS50000000767

• RNA sequencing of untreated head and neck cancer patient-derived xenografts (PDXs) and matched patient tumor tissue.

  RNA sequencing was performed on untreated patient tumor tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to characterize the transcriptional landscape of the tumors in the in vivo setting. 117 total samples were sequenced with paired reads on 10 lanes from different flowcells. They were loaded as 2400 separate files to maintain the data as it was received from BGI - each sample is therefore composed of 5 separate EGAN with 4 files each, adding a 0.1 - .. - 0.5 to each BioSample ID to generate sample aliases. All R1 (and R2, separately) files referring to a BioSample ID should be concatenated to obtain fastq files corresponding to single patients or PDXs.

  Dataset EGAD50000002278

• Whole-exome sequencing (WES) analysis of untreated head and neck cancer patient-derived xenografts (PDXs) matched patient tumor tissue and normal mucosa tissue.

  WES analysis was performed on untreated patient tumor/normal mucosa tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC) to investigate the preservation of tumor-specific genomic alterations in the in vivo context. 183 total samples were sequenced with paired reads on 8-10 lanes from different flowcells. They were loaded as 3538 separate files to maintain the data as it was received from BGI - each sample is therefore composed of 5 separate EGAN with 2-4 files each, adding a 0.1 - .. - 0.5 to each BioSample ID to generate sample aliases. All R1 (and R2, separately) files referring to a BioSample ID should be concatenated to obtain fastq files corresponding to single patients or PDXs.

  Dataset EGAD50000002325

• Molecular classification improves risk assessment in adult B-lineage ALL: Patients on the international UKALLXII-ECOG2993 trial.

  Acute lymphoblastic leukemia (ALL) in adults is a rare disease with outcomes that remain significantly inferior to those of children with ALL. While genomic classification of pediatric B-lineage ALL (B-ALL) has led to improved risk assignment and therapeutic paradigms, similar advances in adults have been lacking. The international UKALLXII/E2993 (NCT00002514) trial accrued over 2000 adult (17-64 years old) patients over 13 years, including 1229 BCR/ABL negative B-ALLs. While 93% of B-ALL achieved a remission, 41% relapsed at a median time of 13 months (Range) and overall survival (OS) at 5 years was 42% (CI). Older age and higher white blood cell (WBC) count at presentation negatively affected OS. Patients with a sibling donor assigned to allogeneic transplantation had superior OS compared to patients without donor. Randomization of patients without a donor showed an advantage of chemotherapy over autologous transplantation in first remission. Transcriptome sequencing of 94% of E2993 patients enabled genomic subtyping. We found that one-third of patients belonged to favorable genotypes (DUX4-rearranged, ETV6-RUNX1, TCF3-PBX1, PAX5 P80R, high hyperdiploidy). Of 63.4% of patients classified as high-risk based age and WBC count at diagnosis, almost 40% harbored subtype-defining genetic associations associated with favorable- or intermediate outcomes. These patients did significantly better than expected from their protocol-defined risk assignment. Our data in a large adult B-ALL cohort treated on a single international trial show the important prognostic value of genomic analysis and the potential benefit for many of the novel genotypes.

  Study EGAS00001004638

• Effectiveness and Safety of Intermittent Antimicrobial Therapy for the Treatment of New Onset Pseudomonas Aeruginosa Airway Infection in Young Patients With Cystic Fibrosis (EPIC-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 investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis (CF) with recently acquired Pseudomonas aeruginosa (PA) infection.Background: CF is an inherited disease that causes mucus to build up in the lungs and digestive tract, which can cause lung infections and digestive problems. It is the most common type of chronic lung disease in children and young adults and may result in early death. There is no cure for this disease. The primary cause of death in individuals with CF is progressive obstructive pulmonary disease associated with chronic Pseudomonas aeruginosa (PA) infection. PA infection can occur early in life and can become highly resistant to antibiotics. Once an individual has been diagnosed with chronic PA infection, it is almost impossible to manage effectively. The need exists for an effective treatment to control and eliminate PA infection. Past research has shown that if PA infection is treated early, there is a greater likelihood that it may be eliminated completely.Participants: There were 304 participants.Design: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of PA - positive cultures.Conclusions: No difference in the rate of exacerbation or prevalence of PA positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits (Arch Pediatr Adolesc Med 2011; 165(9):847-856).

  Study phs004067

• Longitudinal Assessment of Methylmercury and Gut Microbes During Pregnancy

  Methylmercury is a potent neurotoxin, and the fetal period is the most vulnerable exposure period. There is significant variability in methylmercury metabolism, which has been attributed to differences in the structure and function of the gut microbiome. Our main objective was to better understand the interplay between gut microorganisms and methylmercury metabolism during pregnancy. To address this aim, associations were investigated between maternal biomarkers (blood, hair, stool) for prenatal methylmercury exposure and maternal gut microbiota during early and late gestation.

  Study phs001768

• Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP 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 investigate whether the addition of antimicrobial treatments improves outcomes compared to usual care alone among patients with idiopathic pulmonary fibrosis. Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Lung dysbiosis, characterized by increased bacterial load and/or loss of diversity, has been reported in patients with IPF and may contribute to hospitalization and death. Clinical trials investigating other chronic disorders suggest that antimicrobial therapy favorably alters the lung microbial community. The CleanUP IPF study was initiated to determine if an antimicrobial treatment reduces respiratory hospitalization or death among patients with IPF. Participants A total of 513 participants were enrolled. 254 participants were randomized to receive antimicrobials, of those 128 were randomized to receive co-trimoxazole and 126 were randomized to receive doxycycline. 259 participants were randomized to receive usual care alone. Design CleanUP IPF was a randomized, unblinded, multicenter study. Patients were randomized to receive antimicrobials in addition to usual care or usual care alone. Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily) or doxycycline (100 mg once daily if body weight Data collected included diffusion capacity of lungs for carbon monoxide (DLCO), forced vital capacity (FVC), and occurrence of severe adverse events. Several questionnaires were administered to assess quality of life, including the impacts of shortness of breath, fatigue, and chronic cough on participants. The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. The study was terminated early due to futility. Conclusions Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. Martinez FJ, Yow E, Flaherty KR, et al. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA. 2021;325(18):1841-1851. doi:10.1001/jama.2021.4956

  Study phs004314

• Peripheral blood RNA sequencing of samples for a healthy cohort and a cohort with cancer patients

  RNA sequencing (fastq files) of white blood cells (WBCs) from healthy donors (n=376) and cancer patients (n=421) with different diagnoses, stages of disease and previously administered treatments, was performed. Samples from cancer patients were collected from the BostonGene clinical program; all patients provided written consent per IRB-approved protocols. Blood samples from healthy donors were purchased from multiple collection centers throughout the United States. Whole blood samples (3 ml) in K2-EDTA tubes received within 24 hours of collection at RT underwent red blood cell (RBC) lysis to isolate WBCs. Isolated WBCs for RNA sequencing were centrifuged at 300 x g for 5 minutes with a maximum of 10^6 cells per vial. The supernatant was removed, and the cells were resuspended in cold Homogenization Buffer (2% 1-Thioglycerol, Promega). Samples were then frozen at -80°C until extraction. RNA extraction was performed from frozen samples with Maxwell RSC simplyRNA Cells Kit (Promega) using the benchtop automated Maxwell RSC Instrument (Promega). Libraries were prepared with Illumina TruSeq® Stranded mRNA Library Prep (Poly-A mRNA; stranded). Libraries were sequenced on NovaSeq 6000 as Paired-End Reads (2x150) with targeted coverage of 50 mln reads.

  Dataset EGAD50000000414

• Case Report: Precision medicine target revealed by in-vitro modelling of relapsed, refractory ALL from a child with neurofibromatosis

  Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukaemia and acute myeloid leukaemia, but rarely develop B-cell acute lymphoblastic leukaemia (B-ALL). Through in-vitro modelling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signalling, indicative of leukaemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

  Study EGAS00001006187

• Whole Genome Sequencing of INTERVAL (2019-06-12)

  15x Whole Genome Sequencing of 15,000 individuals from the INTERVAL study cohort, phase III. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-06-12.

  Dataset EGAD00001005086

• Australia and New Guinea haplotype phasing (2017-06-27)

  Whole-genome sequencing and phasing of admixed Aboriginal Australian genomes and Papua New Guinean genomes using 10x Genomics Chromium technology. 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/ This dataset contains all the data available for this study on 2017-06-27.

  Dataset EGAD00001003407

• Isotype-resolved sequencing of B-cell receptor in health and disease (2017-09-13)

  Sequencing of B-cell receptor repertoires in healthy individuals and patients with chronic lymphocytic leukemia. 1) 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/ This dataset contains all the data available for this study on 2017-09-13.

  Dataset EGAD00001003748

• Spatially resolved cellular and molecular drivers of cardiac remodelling in healthy and failing human hearts: Adult RNA (2025-07-31)

  Cell Atlas of the diseased human heart. 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 (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2025-07-31.

  Dataset EGAD00001015668

• Breast Cancer - Very young women

  This project will focus on sequencing of breast cancer from young age cancer patients characterized by age at diagnosis under 35. Based on the incidence rate by Korean National Cancer Incidence Database, breast cancer is the most common solid tumors among young adults aged 15-34 excepting thyroid cancer (Cancer statistics in Korea (2012)). This project just started from the mid of 2015. National cancer center in Korea are collecting more than 100 tumor specimens from breast cancer patients aged 20-34. Genetic features of young patients will be investigated with somatic mutation pattern, structural variations, and canonical pathways.

  Study EGAS00001001908

• Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

  The Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer's protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P<5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn's disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

  Study phs000911

• Dynamics of multiple resistance mechanisms in plasma DNA and their clinical implications for NSCLC patients receiving EGFR-targeted therapies

  Background:The development of resistance mechanisms to targeted therapies is complicated by underlying tumour heterogeneity. When multiple resistance mechanisms co-exist, identifying the dominant driver(s) is critical for selection of treatment. Patients and methods:We studied the relative dynamics of multiple oncogenic drivers and resistance mechanisms in 50 patients with EGFR-mutant non-small cell lung cancer (NSCLC), during treatment with gefitinib and hydroxychloroquine (NCT00809237). We performed digital PCR and targeted deep sequencing of cell-free DNA from longitudinal plasma samples from all patients, and shallow whole genome sequencing of serial samples from three patients who underwent histological transformation to small-cell lung cancer (SCLC). ResultsEGFR activating mutations were assessed in tumour samples and accurately identified in plasma samples of 95% of patients (41/43). We identified additional mutations including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%), and PTEN (4/50, 8%), and tracked their relative levels in plasma. Patients with both TP53 and EGFR mutations detected in plasma pre-treatment tended to have worse overall survival than those where only EGFR was detected. The resistance-conferring EGFR T790M mutation was identified in 62% of the patients who progressed. Changes in relative levels of T790M and activating mutations in EGFR corresponded to clinical responses in two patients who were given sequential treatments. Patients who progressed without T790M detected in plasma had worse PFS during TKI continuation, and developed alternative resistance mechanisms, that could be identified in plasma DNA, including SCLC-associated copy number changes and TP53 mutations, that tracked with progression and response to subsequent therapies. Conclusion:Longitudinal analysis of multiple oncogenic drivers in ctDNA may help identifying dominant mechanisms of resistance to EGFR-targeted therapies, and highlight the importance of monitoring genetic events that are not direct drug targets but provide non-invasive molecular information that may guide clinical management.

  Study EGAS00001002908

• Whole Genome Association Study of Systemic Lupus Erythematosus

  The goal of this collaborative study was to identify new genetic risk factors for Systemic Lupus Erythematosus (SLE). To do this we conducted a genome-wide scan by combining the resources and expertise from a number of SLE researchers to establish a large sample set comprising 1311 SLE cases and 3340 controls. The SLE case samples were genotyped from the following collections: 338 subjects from the Autoimmune Biomarkers Collaborative Network (ABCoN), an NIH/NIAMS funded repository, 141 subjects from the Multiple Autoimmune Disease Genetics Consortium (MADGC), 613 subjects from the University of California San Francisco (UCSF) Lupus Genetics, and 335 subjects from the University of Pittsburgh Medical Center (UPMC), plus 8 samples collected at The Feinstein Institute for Medical Research. A total of 3583 control samples were examined in the association analyses. As part of this project, 1861 control samples were selected and then genotyped from the New York Cancer Project (NYCP), based on self-described ethnicity, gender and age. In addition, genotype data from 1722 control samples (all self-described North Americans of European descent) were obtained from the publicly available iControlDB database (http://www.illumina.com/pages.ilmn?ID=231).

  Study phs000122

• Clinical and Molecular Investigation of Familial CEBPA-mutated Acute Myeloid Leukaemia

  Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are clonal diseases arising from the sequential acquisition of genetic aberrations in haematopoietic stem cells. Whilst the aetiology is predominantly sporadic, rare reports describe the autosomal dominant inheritance of MDS and AML (familial MDS/AML), often presenting in younger patients (<40 years of age) with a germline mutation in one of three haematopoietic transcription factors: RUNX1, CEBPA and GATA2. The clinical recognition of familial disease can be challenging due to wide variations in phenotype, latency and transmission, complicated further by the patients’ awareness and reporting of affected relatives. Distinct clinical manifestations have however been reported for each genetic subtype and whilst RUNX1 and GATA2 mutations can harbour prolonged dysplastic or cytopenic phases, germline CEBPA mutations universally present with AML de novo. Our group were the first to describe germline CEBPA mutations in 3 related individuals, all of whom developed AML between 10-30 years of age. The initial pedigree together with those described in the intervening period, were predominantly isolated case reports with limited follow up, hence long term outcomes for this group of patients remain poorly defined. This contrasts with CEBPA mutations occurring in 10-15% of sporadic AML with normal karytoype (NK-AML), where double mutations (CEBPAdm, found in approximately 50% of all CEBPA-AML) are considered a unique molecular entity, associated with favourable clinical outcomes. In sporadic and familial CEBPAdm AML, N’ terminal mutations enforce translation of the shorter P30-kDa isoform and are typically accompanied by C’ terminal insertions or deletions (disrupting the DNA-binding and/or Leucine zipper domains). Definition of the full molecular landscape awaits extensive whole exome sequencing, although GATA2 mutations (targeting the Zinc Finger 1, ZF1, domain) have been reported in 20-40% of sporadic CEBPAdm AML and recent targeted resequencing analysis revealed a further association with WT1 mutations. With minimal clinical and molecular information available for familial CEBPA-AML, we are often consulted regarding the management of this unique patient population. To address this need, we have investigated a multi-centre cohort of families with germline CEBPA mutations, providing extended clinical follow up, whole exome profiling of secondary mutations and molecular analysis of relapsed disease.

  Study EGAS00001000949

• Genomic Studies of Bipolar Disorder in a Large Cohort from The Netherlands

  The transcriptomes of whole blood samples of a large cohort of individuals from the Netherlands were assayed using RNA-seq. These whole blood samples included patients diagnosed with schizophrenia or bipolar disorder, family members of patients, and healthy controls. Within the whole blood dataset, about 600 of the samples were sequenced to an average of 13.9 million mapped reads per sample, while about 2,000 were sequenced to an average of 5.9 million mapped reads per sample, in order to assess changes in power to detect eQTLs based on sample size. We find that expression, defined as the log transcripts per million reads (TPMs), is highly correlated when comparing the moderate (13.9M) and lower (5.9M) coverage datasets. Additionally, a subset of about 150 individuals provided fibroblast cell lines which were assessed for the levels of gene expression using RNA-seq at an average of 50 million mapped reads per sample. We use downsampling techniques to generate synthetic datasets derived from this real fibroblast RNA-Seq data to explore the relationship between coverage and number individuals in an eQTL analysis. Corresponding individual-level genotypes for the samples included in the expression matrix are also made available. The genotypes were derived from multiple other project cohorts, each using different genotyping platforms including OmniExpress Exome, Global Screening Array, Illumina550, and PsychChip. A Plink file set of these cohorts is provided here after merging the separate project file sets and extracting only the individuals who have expression data also provided here; quality control for SNP-missingness is recommended. We demonstrate in this study that given a fixed budget, eQTL discovery power can be increased by lowering the sequencing depth per sample to allow for an a greater number of individuals sequenced. 

  Study phs002856

• Successful Clinical Response in Pneumonia Therapy (SCRIPT)

  The goal of this study is to iteratively identify, validate and refine biomarkers to predict clinical failure, and identify novel targets for therapy, beyond traditional antibiotics, for patients with severe pneumonia requiring intubation, including severe community-acquired pneumonia (CAP), hospital-acquired pneumonia, and ventilator-associated pneumonia (HAP/VAP). We hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution.The major emphasis will be on HAP. Mechanically ventilated CAP patients are a very high-risk group for subsequent VAP, and therefore CAP samples will be included to determine baseline bacteria, microbiome, and host defense patterns for those that do or do not develop HAP/VAP. Hospital-acquired pneumonia is the leading cause of death from nosocomial infections. Even in patients receiving pathogen-appropriate therapy, reported clinical failure rates are increasing, approaching 50% in recent clinical trials. Current approaches to improve outcomes in patients with pneumonia almost exclusively focus on the development of antibiotics to address the problem of resistance. However, the prevalence of antibiotic-resistant pathogens is insufficient to explain the high rates of clinical failure. Instead, we hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution. These factors include pathogen-specific adaptations to the injured lung that modulate the innate and adaptive immune response, as well as changes to the alveolar microbiome, driven by selective pressure within our modern intensive care units. Understanding this complex adaptive system requires the integration of clinical information with unbiased measures of the host, pathogen, and microbiome changes within the alveolar microenvironment. These measures must be repeated over time to identify factors that distinguish successful from failed therapy for pneumonia sufficiently early during the clinical course to allow for effective interventions. To address this challenge, we have assembled a talented group of investigators in the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center. We will leverage our routine clinical practice of safe alveolar sampling in mechanically ventilated patients with pneumonia with repeated non-bronchoscopic bronchoalveolar lavage (NBBAL) sampling over the course of pneumonia. From this fluid, we will combine flow cytometry with multi-omic technologies (cell population-specific transcriptomics, epigenomics, shotgun microbiome sequencing, and pathogen-specific sequencing). Our systems scientists will integrate these genomic data with robust clinical -omics with the goal of identifying biomarkers that can be prospectively tested in patients and causally evaluated in humanized mouse models.The addition of a pooled sample artificially increases the number of automatically computed subjects by one.

  Study phs002300

• bulk RNAseq analysis of tumor from 3 non-muscle-invasive bladder cancer patients

  We performed screenings of patient-specific neo-epitopes by tumor-infiltrating CD8+ T lymphocytes of 4 non-muscle invasive bladder cancer patients. After the tumor resection, these patients went on to receive BCG treatment as they had high-risk disease. In order to select the neo-epitopes, we performed bulk RNAseq of the bladder tumor to select the mutated genes that were expressed in the tumor (TPM >1). For patient UC2, 3 different tumors were resected at the same time and RNA from these 3 tumors were sent separately for RNAseq. For patient UC4, no RNA was available, so this patient is not included in this study.

  Study EGAS50000001383

• Gabriella Miller Kids First Pediatric Research Program in Whole Genome Sequencing of African and Asian Orofacial Clefts Case-Parent Triads

  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. The focus of this study is to identify novel risk variants for OFC in Africa and Asian OFC case-parent triads through analysis of Whole Genome Sequencing data.

  Study phs001997

• Whole genome and transcriptome analysis of medullary thyroid cancer

  Medullary thyroid cancer is the neoplasm of the calcitonin-producing parafollicular cells of the thyroid gland. The hormone calcitonin acts to lower the blood calcium level, counteracting the effects of the parathyroid hormone; it can also serve as a biomarker for the presence or recurrence of medullary thyroid cancer. Surgery is the only curative treatment for this cancer. Targeted therapeutics vandetanib and cabozantinib are approved for the treatment of aggressive and metastatic tumors that are not amenable to surgery. The use of these multikinase inhibitors are supported by the observed overactivation of the RET oncoprotein in a large sub-population of medullary thyroid cancers; however, not all patients carry oncogenic alterations of this kinase. Hence, there is a need for molecular characterization of medullary tumors on the genomic scale with the aim of identifying targetable mutations. Here, we describe the genomic profiles of two medullary thyroid cancers and report the presence of a putative oncogenic BRAF fusion in one. Such alterations previously observed in other malignancies and known targets of available drugs, can benefit patients who currently have no therapy options.

  Study EGAS00001001473

• This dataset contains fastq and BAM data from female adipose tissue.

  Here we have from 64 samples, their corresponding fastq and bam files. The study group consisted of 17 obese women with normal glucose tolerance and 15 obese women with T2DM classified according to WHO standards. The groups were matched for age, BMI and waist circumference. All the women had been morbidly obese (BMI>40 kg/m2) for at least five years.

  Dataset EGAD00001002202

• Anaplastic Thyroid Cancer somatic variants (MuTect)

  Sequence was aligned to the GRCH38 reference genome. Aligned sequence was analyzed with GATK/MuTect, to generate somatic variant calls across the SureSelect All Exon V5+UTR target region. Somatic variant calls are in VCF format. In total there are 166 tumour samples, 94 of which have a matched normal. Somatic variants for tumours without a matched normal, were called against a panel of normals. Details for the mutect call can be found in the vcf header.

  Dataset EGAD00001004129