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• AGLCD sequencing data

  sequencing datasets for AGLCD patient

  Dac EGAC50000000852

• MK Clinical Trial DAC

  DAC for MK Clinical Trial Data

  Dac EGAC50000000677

• DAC_TWINS

  DAC related to monozygotic twins discordant for ALS

  Dac EGAC50000000517

• WGBS and oxBS-seq for APL

  Study EGAS00001005610

• EGAD00010000819

  Summary statistics from meta-analysis for BP phenotypes

  Dataset EGAD00010000819

• Anne Eugster, Center for Regenerative Therapies Dresden, TU Dresden

  Dac EGAC50000000315

• A Genome-Wide Association Study in Participants Experiencing Breast Cancer Events in High-Risk Postmenopausal Women Receiving Selective Estrogen Receptor Modulators on NSABP Trials P-1 and P-2. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The primary aim of this study is to identify genes related to the occurrence of breast events, defined as occurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), in women at high risk of developing breast cancer who have received a Selective Estrogen Receptor Modulator (SERM - tamoxifen or raloxifene) on the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 or P-2 trials. Cases and controls were selected from the tamoxifen arm in the P-1 and from the tamixifen and raloxifene arms in the P-2 trial. For the P-1 trial, cases and controls were required to be 50 years of age or older at time of entry. Cases were females who experienced an invasive breast cancer or DCIS on P-1 or P-2. Controls were females who did not experience an invasive breast cancer or DCIS. A nested matched case-control design was used, with matching on the following factors: 1) trial and treatment arm (P-1 tamoxifen, P-2 tamoxifen, P-2 raloxifene); 2) age at trial entry (when controls could not be exactly matched on age, we incremented the age of matching by +/- 1 year, in sequence until a match was obtained without exceeding +/- 5 years); 5-year predicted breast cancer risk based on the Gail model ( <2.00%, 2.01-3.00, 3.01-5.00, >5.01), 3) history of lobular carcinoma in situ (yes vs. no); 4) history of atypical hyperplasia in breast (yes vs. no); 5) time on study (controls must be on study at least as long as the time to diagnosis of the breast event for the case). Because 94.2% of the participants on P-1 and P-2 treated with tamoxifen or raloxifene were Caucasian, this study was restricted to only Caucasians. Two cases and two controls were randomly chosen as duplicates for quality control of genotype concordance. The DNA samples were plated into 96-well plates, with cases and controls randomly distributed across the plates. A Caucasian parent-child CEPH trio from the HapMap project was included to check for Mendelian transmission of alleles. Genotypes were determined by the RIKEN Center for Genomic Medicine with the Illumina Human610-Quad.

  Study phs000305

• Projects

  Projects Jointly managed by the European Bioinformatics Institute (EMBL-EBI) in Cambridge (UK) and the Centre for Genomic Regulation (CRG) in Barcelona, the EGA provides an invaluable service to the worldwide biomedical research community. The teams leading the EGA are involved in several international partnerships and consortia in numerous scientific fields, where they contribute to ambitious projects. In addition to the project listed below, the EGA is in a long-standing partnership with the Global Alliance for Genomics and Health (GA4GH), as described on the dedicated page. On-going projects Project Duration Domain Funder Tags CANDLE | CANDLE project aims to conceptualise and advance the development of National Cancer Data Nodes (NCDNs) in European countries. These NCDNs will boost the reuse of cancer data for research, innovation and policy making, in order to improve diagnostics and treatment for cancer patients, as well as prevention and early detection. 2025-2028 Cancer Horizon Europe DOCUMENTATION EASIGEN-DS | The EASIGEN-DS project aims to conduct a design study to establish a new European Research Infrastructure on Advanced Genomics Technologies, EASIGEN. To develop an excellent scientific, technological and operational design, we will conduct landscape studies, stakeholder consultations, and community surveying. 2025-2028 Genomic and health data Horizon Europe DATA MANAGEMENT DOCUMENTATION INFRASTRUCTURE Go-IMPaCT | Go-IMPaCT will contribute sequenced genomes and provide infrastructure as part of IMPaCT-Cohort, one of the three fundamental pillars of the Precision Medicine Infrastructure associated with Science and Technology (IMPaCT) program in Spain. Along with the Genome of Europe (GoE) project, around 18.000 people will have their genomes sequenced, also contributing to Spain's commitments in 1+MG. Go-IMPaCT will fund the development of an EGA node to manage and share this genomic and phenoclinic data, laying the foundations for regional and ethnic genomic variability in Spain to be available for research purposes. The IMPaCT cohort is created with the spirit of being an open research tool, compatible with the rest of the health research ecosystem, and other international initiatives. 2025-2027 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS FAIR-FEGA | This project seeks to accelerate data depositions into FEGA, significantly increasing the data flow in and from FEGA nodes. It will build capacity within the FEGA nodes and increase awareness in a wide range of stakeholders, thus altogether achieving the ultimate goal of enhancing data reuse. The project will be carried out by a strategic consortium comprising seven ELIXIR nodes and two ELIXIR communities. 2025-2026 Not applicable ELIXIR ACCESS DISCOVERY DOCUMENTATION INFRASTRUCTURE METADATA STANDARDS FEGA-Connect | A consortium of six ELIXIR nodes plus the Polish FEGA node (in-kind contribution) joining forces to build a solid base to develop solutions for effective multi-omic sensitive data integration between FEGA nodes and other infrastructures and specialised Data repositories. We aim to promote a more coherent data deposition, discoverability and retrieval of multi-omics datasets, providing FAIRer data and consequently accelerating research. 2025-2026 Multi-omics data ELIXIR ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE METADATA STANDARDS IMPaCT-Data 2 | IMPaCT-Data 2 will develop a digital platform for the integration and modelling of biomedical data associated with IMPaCT (Precision Medicine Infrastructure associated with Science and Technology) projects in Spain. It will deploy a sustainable infrastructure that facilitates the integration, standardisation, interoperability and analysis of clinical, genomic, molecular and medical imaging data. This platform will be aligned with European projects such as Genome of Europe (GoE), the first project to make use of the European Genomic Data Infrastructure (GDI), and EUCAIM. IMPaCT-Data 2 will benefit from advanced Artificial Intelligence and High Computing Capacity Systems capabilities, offering robust and accessible tools for researchers from the National Health System in Spain. 2025-2026 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS SenSec | This project aims to establish a mechanism for orchestrating secure access to sensitive data hosted by the EGA, whether in Central EGA or any Federated Node, from Galaxy, a popular open-source, community-driven VRE (Virtual Research Environment) for bioinformatics analysis. Building on a previous prototype that enabled Galaxy users within Trusted Research Environments (TREs) to decrypt sensitive data for workflow execution without sharing private encryption keys, SenSec will expand this prototype into a comprehensive solution for secure data analysis in Galaxy, facilitating encrypted data access and transfer from FEGA/EGA repositories to designated TREs. 2025-2026 Genomic and health data; trusted research environment ELIXIR ACCESS DATA ANALYSIS ERDERA | The European Rare Disease Research Alliance (ERDERA) takes over EJPRD to deliver concrete health benefits to rare disease patients in the next decade by advancing prevention, diagnosis and treatment research. To leave no one behind, over 170 organisations championed by the European Union and member states are working hand in hand to make Europe a world leader in rare diseases research and innovation. 2024-2034 Rare diseases Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution ACCESS DATA ANALYSIS DISCOVERY INFRASTRUCTURE SYNTHIA | The aim of SYNTHIA is to deliver validated, reliable tools and methods for synthetic data generation (SDG). The tools will cover multiple data types including lab results, clinical notes, genomics, imaging and m-health data. SYNTHIA also hopes to make possible the generation of longitudinal data. 2024-2029 Genomic and health data; multi-omics; AI solutions Innovative Health Initiative (IHI) DATA ANALYSIS DATA MANAGEMENT INFRASTRUCTURE GoE | The Genome of Europe initiative aims to build a European network of national genomic reference cohorts of at least 500.000 citizens. These reference cohorts will be selected to be representative of the European population. 2024-2028 Large-scale genomic and health data Horizon Europe ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS HEREDITARY | HEREDITARY aims to transform the way we approach disease detection, prepare treatment response, and explore medical knowledge by building a robust, interoperable, trustworthy, and secure framework that integrates multimodal health data (including genetic data) while ensuring compliance with cross-national privacy-preserving policies. 2024-2027 Neurodegenerative disorders, gut-brain interplay Horizon Europe DATA MANAGEMENT DATA ANALYSIS EOSC-ENTRUST | The mission of EOSC-ENTRUST is to create a European network of trusted research environments for sensitive data and to drive European interoperability by joint development of a common blueprint for federated data access and analysis. 2024-2026 Trusted Research Environment Horizon Europe INFRASTRUCTURE EBV-MS | "Targeting Epstein-Barr Virus Infection for Treatment and Prevention of Multiple Sclerosis". The ambitious goals of the project are to answer the questions why only a few EBV infected persons develop MS, and define the underlying mechanism of this process, as well as clarify if targeting the EBV infection can prevent MS or improve the disease course. 2023-2028 Viral-host genetics; immune response; disease modelling; disease prevention; AI/ML solutions Horizon Europe DATA MANAGEMENT DATA ANALYSIS WISDOM | WELL-BEING IMPROVEMENT THROUGH THE INTEGRATION OF HEALTHCARE AND RESEARCH DATA AND MODELS WITHOUT BORDER FOR CHRONIC IMMUNE-MEDIATED DISEASES aims to deploy novel approaches for data processing, harmonisation, management, and secure data sharing and federated access for diseases like multiple sclerosis. Using an end-user guided approach, it will facilitate responsible and critical assessment of the use of AI in healthcare. 2023-2028 Chronic immune-mediated diseases Horizon Europe DATA MANAGEMENT INFRASTRUCTURE EUCAIM | EUropean Federation for CAncer IMages is a project that will build a highly secure, federated and large-scale European cancer imaging platform, with capabilities that will greatly enhance the potential of Artificial Intelligence in oncology. 2023-2027 Cancer Digital Europe Programme (DIGITAL) DISCOVERY CONTAGIO | CONTAGIO (COhorts Network To be Activated Globally In Outbreaks) aims to create coordination mechanisms to rapidly react to infectious disease (re-)emergence in low- and middle-income countries (LMICs). 2023-2026 Infectious Diseases European Commission - Horizon Europe ACCESS DATA MANAGEMENT DISCOVERY Youth-GEMs | Youth-GEMS (Gene Environment Interactions in Mental Health TrajectorieS of Youth) will conduct research into the genetic and environmental factors of mental health in young European people. 2022-2027 Mental health European Commission - Horizon Europe DATA MANAGEMENT DISCOVERY GDI | The European Genomics Data Infrastructure project is enabling access to genomic and related phenotypic and clinical data across Europe. It is doing this by establishing a federated, sustainable and secure infrastructure to access the data. 2022-2026 Genomic and health data European Commission - Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution DISCOVERY DOCUMENTATION INFRASTRUCTURE IMPaCT-T2D | The IMPaCT-T2D project aims at studying the complete genomes of a large cohort of patients with Type 2 Diabetes mellitus (T2D), using modern sequencing technologies and artificial intelligence (AI) in order to improve the stratification and pharmacological treatment in the context of precision medicine. 2022-2025 Cardiovascular and Complex Diseases Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE Completed projects Project Duration Domain Funder Tags EOSC4Cancer | EOSC4Cancer builds on existing projects, research outcomes and established community solutions to create the federated FAIR data, analysis and services infrastructure needed for European Cancer research programmes. 2022-2025 Cancer European Commission - Horizon Europe DISCOVERY EuCanImage | A European Cancer Image Platform Linked to Biological and Health Data for Next-Generation Artificial Intelligence and Precision Medicine in Oncology. 2020-2025 AI Solutions in Oncology European Commission - H2020 Programme; "La Caixa" Foundation cofunds CRG's contribution DATA MANAGEMENT METADATA STANDARDS GenoMed4ALL | A consortium built to empower personalised medicine in the field of haematological diseases through the use of AI and the pooling of genomic and clinical data. 2020-2025 Hematological diseases European Commission - H2020 Programme DISCOVERY METADATA STANDARDS BY-COVID | The BeYond-COVID project aims to make COVID-19 data accessible to scientists in laboratories but also to anyone who can use it, such as medical staff in hospitals or government officials. Going beyond SARS-CoV-2 data, the project will provide a framework for making data from other infectious diseases open and accessible to everyone. 2021-2024 Infectious diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE IMPaCT-Data | IMPaCT-Data aims to create the infrastructure for secondary use of data from Spanish healthcare systems - electronic health records, medical imaging and genomic repositories - and contribute with the knowledge and methodology produced to the healthcare system. 2021-2024 Large-scale genomics and health dataSpanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE LaMarato | It is a project aimed at creating and developing a catalan interhospitalary network to interrogate genetic variants from thousands of genetic tests carried out in patients with rare diseases from the main catalan hospitals. 2021-2024 Genomic and health data Fundacio La Marato de TV3 (catalan foundation) DISCOVERY HealthyCloud | This consortium will contribute a Strategic Agenda towards the European Health Research and Innovation Cloud. The project will work in collaboration with a broad range of stakeholders to ensure that all voices are included and that the results are technically and ethically sound. 2021-2023 Not Applicable European Commission - H2020 Programme DOCUMENTATION B1MG | Beyond 1 Million Genomes aims to create a network of genetic and clinical data across Europe. The project provides coordination and support to the 1+ Million Genomes Initiative (1+MG). This initiative is a commitment of 24 EU countries, the UK and Norway to give cross-border access to one million sequenced genomes by 2022. 2020-2023 Not applicable European Commission - Horizon Europe DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS ELIXIR-CONVERGE | An alliance with the goal of Connecting and aligning ELIXIR Nodes to deliver sustainable FAIR life-science data management services. 2020-2023 Data Management and Infectious Diseases European Commission - H2020 Programme DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS IHCC | The International HundredK+ Cohorts Consortium aims to create a global platform for translational research ? informing the biological and genetic basis for disease and improving clinical care and population health. 2020-2022 Translational research NIH; The Wellcome Trust; CZI INFRASTRUCTURE METADATA STANDARDS PPCG | The Pan Prostate Cancer Group aims to harmonise and interrogate Whole Genome DNA Sequence data generated around the world from over 2000 men with prostate cancer, with associated transcriptome and methylome data to include men from different clinical categories, and ethnicities. This project is about providing breakthrough advances through analysis of a very large series of Whole Genome DNA data from prostate cancer contributed by many of the leading scientists and clinicians working in prostate cancer genomics. 2019-2024 Cancer Cancer Research UK DATA MANAGEMENT CINECA | Consortium providing a Federated solution enabling population-scale genomic and biomolecular data accessible across international borders accelerating research and improving the health of individuals resident across continents. 2019-2023 Large-scale Genomics and Health Data European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE EASI-Genomics | A project designed to provide easy access to cutting-edge DNA sequencing technologies to researchers from academia and industry, within a framework that ensures compliance with ethical and legal requirements, as well as FAIR and secure data management. 2019-2023 Next Generation Sequencing European Commission - H2020 Programme ACCESS EJP-RD | An European consortium built to create a comprehensive, sustainable ecosystem allowing a virtuous circle between research, care, and medical innovation. 2019-2023 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DOCUMENTATION METADATA STANDARDS EOSC-Life | EOSC-Life brings together the 13 Life Science research infrastructures (LS RIs) to create an open, digital and collaborative space for biological and medical research. The project will publish 'FAIR' data and a catalogue of services provided by participating RIs for the management, storage and reuse of data in the European Open Science Cloud (EOSC). 2019-2023 Not applicable European Commission - H2020 Programme DOCUMENTATION EUCANCan | A federated network aiming at implementing a cultural, technological and legal integrated framework across Europe and Canada, to enable and facilitate the efficient sharing of cancer genomic data. 2019-2023 Cancer European Commission - H2020 Programme DATA MANAGEMENT METADATA STANDARDS The Federated EGA framework: supporting sensitive data management across the ELIXIR Nodes | This project is a direct continuation of the FHD IS with the goal to position the FEGA framework as the core infrastructure driver to support human data sharing for research. 2019-2023 Human genomic data ELIXIR INFRASTRUCTURE UK Biobank | UK Biobank is a large-scale biomedical database and research resource, containing in-depth genetic and health information from half a million UK participants. This project is to archive whole genome sequencing and other genetic data for UK Biobank participants. 2019-2023 Large-scale Genomics and Health Data The Wellcome Trust; UKRI; Amgen; AstraZeneca; GSK; Johnson & Johnson DATA MANAGEMENT INFRASTRUCTURE VEIS | The core mission of VEIS is to create an open ecosystem of technologies that will address and adapt to the requirements of the systems used to analyse and interpret -omics and clinical data in research and application environments in biomedicine. The aim of the project is to leverage the value of the EGA for both industry and society. 2019-2022 Oncology and Rare diseases Generalitat de Catalunya and European Regional Development Fund (ERDF) ACCESS DISCOVERY ELIXIR BEACON IS | This study follows on from a number of earlier activities that have established the ELIXIR Beacon Project. The main aim is to extend the Beacon protocol, developed at EGA, to become the reference ELIXIR Data Discovery product 2019-2021 Not applicable ELIXIR DISCOVERY ELIXIR FHD IS | This project coordinates the delivery of FAIR compliant metadata standards, interfaces, and reference implementation to support the federated ELIXIR network of human data resources. 2019-2021 Human genomic data ELIXIR INFRASTRUCTURE ELIXIR Rare Disease | The Rare Disease Community extends and generalises the system of access authorisation and high volume secure data transfer developed within the EGA. The goal of the Community is to create a federated infrastructure that will enable researchers to discover, access and analyse different rare disease repositories across Europe. It is doing this in partnership with other European infrastructure projects, namely RD-CONNECT, BBMRI-ERIC and E-Rare.2019-2021 Rare diseases ELIXIR INFRASTRUCTURE Solve-RD | Solve-RD - solving the unsolved rare diseases - is a research project funded by the European Commission. It echoes the ambitious goals set out by the International Rare Diseases Research Consortium (IRDiRC) to deliver diagnostic tests for most rare diseases by 2020. The current diagnostic and subsequent therapeutic management of rare diseases is still highly unsatisfactory for a large proportion of rare disease patients - the unsolved RD cases. For these unsolved rare diseases, we are unable to explain the etiology responsible for the disease phenotype, predict the individual disease risk and/or rate of disease progression, and/or quantitate the risk of relatives to develop the same disorder. 2018-2024 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT METADATA STANDARDS EuCanShare | An EU-Canada joint infrastructure for next-generation multi-Study Heart research. 2018-2022 Cardiovascular Diseases European Commission - H2020 Programme ACCESS METADATA STANDARDS

  Documentation about/projects-and-funders/projects

• NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)

  The Cleveland Family Study is the largest family-based study of sleep apnea world-wide, consisting of 2284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study was begun in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. NIH renewals provided expansion of the original cohort (including increased minority recruitment) and longitudinal follow-up, with the last exam occurring in February 2006. Index probands (n=275) were recruited from 3 area hospital sleep labs if they had a confirmed diagnosis of sleep apnea and at least 2 first-degree relatives available to be studied. In the first 5 years of the study, neighborhood control probands (n=87) with at least 2 living relatives available for study were selected at random from a list provided by the index family and also studied. All available first degree relatives and spouses of the case and control probands also were recruited. Second-degree relatives, including half-sibs, aunts, uncles and grandparents, were also included if they lived near the first degree relatives (cases or controls), or if the family had been found to have two or more relatives with sleep apnea. Blood was sampled and DNA isolated for participants seen in the last two exam cycles (n=1447). The sample, which is enriched with individuals with sleep apnea, also contains a high prevalence of individuals with sleep apnea-related traits, including: obesity, impaired glucose tolerance, and HTN. Phenotyping data have been collected over 4 exam cycles, each occurring ~every 4 years. The last three exams targeted all subjects who had been studied at earlier exams, as well as new minority families and family members of previously studied probands who had been unavailable at prior exams. Data from one, two, three and four visits are available for 412, 630, 329 and 67, participants, respectively. In the first 3 exams, participants underwent overnight in-home sleep studies, allowing determination of the number and duration of hypopneas and apneas, sleep period, heart rate, and oxygen saturation levels; anthropometry (weight, height, and waist, hip, and neck circumferences); resting blood pressure; spirometry; standardized questionnaire evaluation of symptoms, medications, sleep patterns, quality of life, daytime sleepiness measures and health history; venipuncture and measurement of total and HDL cholesterol. The 4th exam (2001-2006) was designed to collect more detailed measurements of sleep, metabolic and CVD phenotypes and included measurement of state-of-the-art polysomnography, with both collection of blood and measurement of blood pressure before and after sleep, and anthropometry, upper airway assessments, spirometry, exhaled nitric oxide, and ECG performed the morning after the sleep study. Data have been collected by trained research assistants or GCRC nurses following written Manuals of Procedures who were certified following standard approaches for each study procedure. Ongoing data quality, with assessment of within or between individual drift, has been monitored on an ongoing basis, using statistical techniques as well as regular re-certification procedures. Between and within scorer reliabilities for key sleep apnea indices have been excellent, with intra-class correlation coefficients (ICCs) exceeding 0.92 for the apnea-hypopnea index (AHI). Sleep staging, assessed with epoch specific comparisons, also demonstrate excellent reliability for stage identification (kappas>0.82). There has been no evidence of significant time trends-between or within scorers- for the AHI variables. We also have evaluated the night-to-night variability of the AHI and other sleep variables in 91 subjects, with each measurement made 1-3 months apart. There is high night to night consistency for the AHI (ICC: 0.80), the arousal index (0.76), and the % sleep time in slow-wave sleep (0.73). We have demonstrated the comparability of the apnea estimates (AHI) determined from limited channel studies obtained at in-home settings with in full in-laboratory polysomnography. In addition to our published validation study, we more recently compared the AHI in 169 Cleveland Family Study participants undergoing both assessments (in-home and in-laboratory) within one week apart. These showed excellent levels of agreement (ICC=0.83), demonstrating the feasibility of examining data from either in-home or in-laboratory studies for apnea phenotyping. Data collected in the GCRC were obtained, when possible, with comparable, if not identical techniques, as were the same measures collected at prior exams performed in the participants' homes. To address the comparability of data collected over different exams, we calculated the crude age-adjusted correlations ~3 year within individual correlations between measures made in the most recent GCRC exam with measures made in a prior exam and demonstrated excellent levels of agreement for BMI (r=.91); waist circumference (0.91); FVC (0.88); and FEV1 (0.86). As expected due to higher biological and measurement variability, 149 somewhat lower 3-year correlations were demonstrated for SBP (0.56); Diastolic BP (0.48); AHI (0.62); and nocturnal oxygen desaturation (0.60). NHLBI Candidate-gene Association Resource. The NHLBI initiated the Candidate gene Association Resource (CARe) to create a shared genotype/phenotype resource for analyses of the association of genotypes with phenotypes relevant to the mission of the NHLBI. The resource comprises nine cohort studies funded by the NHLBI: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Cleveland Family Study (CFS), Coronary Artery Risk Development in Young Adults (CARDIA), Cooperative Study of Sickle Cell Disease (CSSCD), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). A database of genotype and phenotype data will be created that includes records for approximately 50,000 study participants with approximately 50,000 SNPs from more than 1,200 selected candidate genes. In addition, a genome wide association study using a 1,000K SNP Chip will be conducted on approximately 9,500 African American participants drawn from the 50,000 participants in the nine cohorts. Some relevant CARe publications CARe Study: PMID 20400780 CVD Chip Design: PMID 18974833

  Study phs000284

• NHLBI TOPMed: Outcome Modifying Genes in Sickle Cell Disease (OMG)

  Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the pathophysiologic processes of vaso-occlusion and hemolysis. These pathophysiological processes are complex and expected to impact multiple organ systems in a variety of ways. This study, therefore, was designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We enrolled > 700 patients with Hb SS, Hb S-beta0 thalassemia and HbSC being followed primarily at three southeastern U.S. regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained included the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). Clinical data include medical status (history, physical, examination, and laboratory results) and information regarding potentially confounding environmental factors. Limited plasma samples are available for correlative studies (e.g. of cytokine levels, coagulation activation). Targeted SNP for candidate gene analysis as well as GWAS has been performed on most samples. Whole genome sequencing has been conducted through the TOPMed Consortium. The subjects in this analysis were collected as part of a larger study, "Outcome Modifying Genes in Sickle Cell Disease" (OMG-SCD) aimed at identifying genetic modifiers for sickle cell disease. More information about the study can be found in Elmariah et al. (2014), PMID: 24478166. Clinical and genetic data have been used to identify genetic characteristics predisposing patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. It is anticipated that identification of such genetic factors will reveal new therapeutic targets individualized to specific complications of SCD, leading to improved outcomes and increased life expectancy for patients with SCD.

  Study phs001608

• Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

  Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence and the lifetime cost of care per individual, in the range of $1-2 million in United Sates (CDC), it presents a significant health burden. Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However, the identity of a large number of essential molecular and cellular components still remain elusive. The objectives of our study are to expand the genetic repertoire of causal ID genes and characterize their role in neuronal structure and cognitive function. The rationale is that identification and functional elucidation of causative gene variants that lead to cognitive dysfunction will be essential for understanding brain function and for developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders, including ID. There are 3 aims of our comprehensive research program: 1) Ascertain and clinically phenotype members of extended families segregating autosomal recessive intellectual disability (ARID); 2) identify new ARID genes and gene products; and 3) determine the functions of prioritized novel ARID genes using multifaceted approaches, including analysis of spatiotemporal expression patterns in mouse brain, targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology and live-cell imaging assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutic targets to slow progression, delay onset, and possibly devising precision medicine approaches for ID.

  Study phs003298

• Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

  Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

  Study phs001228

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

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

  Study phs002514

• Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

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

  Study phs000653

• German early-onset prostate cancer cohort of the Pan-Prostate Cancer Genome (PPCG) project

  Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected. Prostate cancer is generally considered a tumor of elderly men. However, a fraction of prostate cancers are diagnosed at the age of 55 years or less. For several reasons, these “early onset prostate cancers” may represent a key entity for the understanding of prostate cancer biology. First, it is likely that early onset prostate cancers represent a distinct molecular subgroup of prostate cancer (PCa), potentially characterized by relatively small numbers of genetic changes, some of which may be particularly strong driver mutations for PCa development. Second, a fraction of prostate cancers in young individuals could represent classical prostate cancers that are detected at a very early stage and might therefore have accumulated molecular changes/mutations occurring that are most instrumental for prostate cancer early detection. Third, PCa with hereditary backgrounds are likely to accumulate in the age group below 55 years. A comparison with other sample sets (e.g. from other ICGC consortia), a systematic genomic analysis of young men with PCa could therefore lead to the detection of mechanisms for hereditary PCa. Fourth, a better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients. We are analyzing the entire genomic DNA sequences of at least 200 PCas (and matched non-tumorous DNA) of young men (≤ 55y), to at least 30 fold coverage, and integrate single-nucleotide variants and genomic structural variations with differential methylation, mRNA and miRNA expression data.Tissues were collected at the University Medical Center Hamburg-Eppendorf. Sequencing was performed at DKFZ and NCT (Heidelberg), EMBL (Heidelberg), and MPIMG (Berlin). Data management and bioinformatic data analyses is being conducted at DKFZ.

  Study EGAS00001003373

• Drug development for pediatric cancers: the importance of patient' s genomic data re-use

  Cancer in children is uncommon and the overall prognosis for most pediatric cancers is good. However, while the combined survival rates have improved over the last decades, certain childhood malignancies, such as high-grade gliomas or metastatic sarcomas, still remain incurable in most patients. New strategies for targeting those devastating diseases are imperative, and patient genomic data can become a key asset in the process [1]. The Pediatric Cancer Genome Project’s datasets At EGA, we store over 500 datasets with sequencing data from pediatric cancer patients. A remarkable case is the datasets belonging to the Pediatric Cancer Genome Project (PCGP) from St. Jude Children’s Research Hospital–Washington University (Table 1 - EGAS list). PCGP is an ambitious effort to identify the mutations that drive childhood cancer and find new cures. Those datasets include 600 patients with complete tumor and normal genomes from 15 different tumor types. PCGP datasets have been an important resource for various studies that pooled genomic data from different public and in-house datasets to perform extensive genomic characterizations and publish comprehensive pan-cancer pediatric studies [2],[3]. Other interesting pediatric cancer datasets are from the Pediatric Brain Tumor Consortium, Sickkids or ICGC PedBrain project. How data reuse impacts drug development for pediatric cancers Recently, in October 2024, Nature Communications published a work led by the University of Michigan where authors used data from EGA (PCGP) check the table below as part of their strategy to pursue the identification of new tumor vulnerabilities susceptible to becoming novel therapeutic targets in diffuse midline glioma. Diffuse midline gliomas (DMG) are treatment-resistant and uniformly fatal pediatric brain tumors. The prognosis of this brainstem tumor is dismal with a median overall survival of 9–12 months from diagnosis. In this study, the authors first developed a lab model of the disease and reanalyzed data from the EGA to identify genes potentially linked to tumor severity. This approach revealed involvement of specific metabolic pathways, suggesting new possibilities for therapeutic intervention. In mice, the study shows that the use of statins can improve survival. For a brief overview of the underlying science, diffuse midline gliomas present intratumor heterogeneity with subpopulations of less-differentiated oligodendrocyte precursors and more differentiated astrocytes. Authors established in vitro models to recapitulate both phenotypes and identify metabolic programs in both subpopulations. To determine the clinical relevance, the authors re-used gene expression data from 76 DMG patients identifying a gene signature predicting decreased overall survival. After extensive metabolic characterization of subpopulations, authors defined strategies to target specific metabolic vulnerabilities. Pre-clinical experiments in mice using OXPHOS inhibitors and statins showed a reduction in tumor burden and increased overall survival [4]. In this scenario, the re-use of high-quality patient’s sequencing data appeared as an advantageous strategy to support the clinical relevance of in-vitro and pre-clinical findings. On the other hand, in rare conditions such as childhood cancer, the availability of public datasets and the possibility of pooling data from different sources can be the only way to obtain impactful results that lead to improvements for patients. References Davidoff, A. M. Pediatric Oncology. Seminars in pediatric surgery 19, 225–233 (2010). Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). Venu Thatikonda et al. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. Nature Cancer 4, 276–289 (2023). Mbah, N. E. et al. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nature Communications 15, (2024). Datasets and Studies ID Title Access Policy Year EGAD00001000134 Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAS0000100192 Somatic Histone H3 Mutations in Diffuse Intrinsic Pontine Gliomas and Non-Brainstem Paediatric Glioblastomas St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project 2017 EGAS00001000575 Whole genome sequencing and whole exome sequencing of DIPG tumors and matched normal tissue The hospital for sick children ("SickKids") 2016 EGAD00001000792 Exome sequencing reads of paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAD00001002006 Whole genome sequencing of paediatric glioblastoma in the ICGC PedBrain project ICGC PedBrain project 2016

  Blog drug-development-for-pediatric-cancers

• Download Metadata

  Metadata Distribution Welcome to the realm of Metadata Distribution within the EGA ecosystem! Our Metadata REST API empowers you to effortlessly retrieve metadata from the expansive landscape of EGA. By utilising this API, you gain access to publicly available insights across various EGA domains, including studies, samples, experiments, runs, analyses, policies, DACs, and datasets. Furthermore, this API facilitates cross-referencing of objects, enabling you to gather, for example, all the datasets associated with a specific DAC, seamlessly. In addition, we have added the ability to query private data using the metadata API. If you possess the necessary permissions, you can access behind-the-login private data for a specified list of datasets. Metadata Distribution Index Identifiers Dataset Mappings Website Download Metadata API - Private Identifiers At the core of EGA's organisational structure are unique accessions that serve as essential tags for our diverse objects. Here's a quick overview of the accessions and their corresponding object types: EGA Accession ID EGA Object description EGAS EGA Study Accession ID EGAC EGA DAC Accession ID EGAP EGA Policy Accession ID EGAN EGA Sample Accession ID EGAR EGA Run Accession ID EGAX EGA Experiment ID EGAZ EGA Analysis Accession ID EGAD EGA Dataset Accession ID EGAB EGA Submission ID EGAF EGA File Unique Accession ID For further information check our metadata schema documentation. Dataset Mappings For authorised datasets, comprehensive mappings reveal meaningful connections: Sample_file: This file presents information about the linkage between samples and files available in the dataset. Study_experiment_run_sample: This file presents information about the linkage between studies, experiments, runs, and samples within the dataset. Study_analysis_sample: This file presents information about the linkage between studies, analyses, and samples contained within the dataset. Run_sample: This file presents information about the linkage between runs and samples within the dataset. Analysis_sample: This file presents information about the linkage between analyses and samples within the dataset. An empty file indicates the absence of corresponding information. Website Download Our website serves as your gateway to downloading metadata. Simply navigate to the dataset page, and you'll find a blue Metadata button. Once authenticated, you can click this button for authorised datasets. If you lack permissions for a particular dataset, request access by clicking the 'Request Access' button. For authorised datasets, choose your preferred metadata format: CSV, TSV, or JSON. Metadata API - Private Leverage the power of programmatic metadata downloads! Start by authenticating yourself with your credentials to obtain an access token. With this token, programmatically query private information. Queries mirror the structure of the Public Metadata API. However, behind the login, you can delve into specific mapping information (as mentioned above in dataset mappings) alongside object-level exploration. Authentication An active session is required to work with the API. Each time you log in with your credentials a new session is started, which is identified by an access_token. Below an example on how to obtain one using curl: curl https://idp.ega-archive.org/realms/EGA/protocol/openid-connect/token \ -d 'client_id=metadata-api' \ -d 'username=...' \ --data-urlencode 'password=...' \ -d 'grant_type=password' All responses from the API are in JSON format. A successful response should include a new token to be used for the session: {"access_token":"eyJhbGciOiJSUzI1NiIsInR5cCIgOiA...TNw", "expires_in":300, "refresh_expires_in":1800, "refresh_token":"eyJhbGciOiJIUzI1NiIsInR5cCIgOiA...pTX10", "token_type":"Bearer", ... } Save the access_token value and include it in the API call headers. Example query usage Below you can find some example of queries available behing authentication and authorisation. Querying study-experiment-run-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/study_experiment_run_sample \ -H 'Authorization: Bearer access_token' Querying run-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/run_sample \ -H 'Authorization: Bearer access_token' Querying study-analysis-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/study_analysis_sample \ -H 'Authorization: Bearer access_token' Querying analysis-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/analysis_sample \ -H 'Authorization: Bearer access_token' Querying sample-file mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/sample_file \ -H 'Authorization: Bearer access_token' You can get a different output format by adding one of these options to the curl command: -H 'Accept: text/tsv' -H 'Accept: application/json' -H 'Accept: text/csv' For more detailed information, refer to the Metadata API Specification.

  Documentation access/download/metadata

• UK10K NEURO GURLING

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

  Study EGAS00001000225

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• Effects of 2DG, Galactose, or Oligomycin on the epigenome remodeling induce by T cells activation.

  T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.

  Study EGAS00001007115

• Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance

  Background Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states. Methods We exposed human primary monocytes from healthy donors (n=6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2hr) and two models of endotoxin tolerance: repeated stimulations (6+6hr) and prolonged exposure to endotoxin (24hr). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing. Results We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24-29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6884 of 34616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving FCHO1 and coronary artery disease. Conclusion This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.

  Study EGAS00001007362

• Method to Assess Lung Water Accumulation During Exercise

  The goal of this non-significant risk medical device study is to test the initial technical feasibility of a 0.55T MRI in healthy volunteers by technical optimization of scanner protocols, and to test accuracy of standard MR measurements in adult patients with known stable disease. Exercise-induced lung water is a key feature in heart failure. Dynamic quantitative lung water imaging during exercise stress is therefore of interest to unmask latent heart failure. We developed a novel magnetic resonance imaging (MRI) method using a proton density weighted ultrashort echo time MRI sequence along with a time-resolved and respiratory motion compensated image reconstruction for exercise lung water imaging. We validated our method in a porcine model of dynamic lung water accumulation (n=5), and tested its feasibility for use in humans using 12 healthy subjects, 1 patient with heart failure with preserved ejection fraction, and 1 patient with heart failure with reduced ejection fraction. Data suggest the novel imaging method is capable of dynamically imaging lung water accumulation during exercise stress. Reference 1 (PMID: 37288601) contains the main results for this study.

  Study phs003346

• A Study of the Genetic Causes of Complex Pediatric Disorders

  The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic medical records (EMRs). EMRs are longitudinal, with a mean duration of 6.5 years. CAG has committed to releasing genotype and phenotype data for 4000 individuals diagnosed with asthma, ADHD, atopic dermatitis, GERD (1000 for each), and 1000 individuals on the upper and lower ranges of Low-Density Lipoprotein (LDL) levels to dbGaP. We will also release genotype/phenotype of 3000 controls. Relevant phenotype data includes primary diagnoses (ICD9 codes), secondary diagnoses (ICD9 codes), medical procedures/tests conducted in relation to the phenotype, and a listing of relevant medications. Further details of CAG's research programs and capacity are available at: http://www.caglab.org

  Study phs000490

• Next Generation Mendelian Genetics: Neonatal Diabetes

  The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

  Study phs000542

• SNPs and Extent of Atherosclerosis (SEA) Study

  The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.

  Study phs000349

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• Genome-Wide Discovery of Novel Breast Cancer Predisposing Mutations

  Cancer risk shows clear heritability, but the inherited genetic factors remain largely unknown. This project will seek to identify new genes in which mutations confer hereditary risk for early onset breast cancer, with important implications for both biological understanding and clinical prediction and prevention. Identifying cancer predisposing mutations can provide new biological insights and significantly impact important clinical decision making regarding treatment, surveillance and preventive approaches. Examples include the BRCA1 breast cancer susceptibility gene, which affects treatment decisions (surgical management), surveillance (frequent breast MRI) and prevention (oophorectory for prevention of ovarian cancer). Hereditary early onset breast cancer patients commonly present to Cancer Genetics clinics, but the majority of these patients do not have identifiable mutations in known candidate genes. Here, we will perform whole exome sequencing to discover novel cancer susceptibility genes. The patients have been recruited from Memorial Sloan Kettering Cancer Center (PIs Kenneth Offit and Zsofia Stadler) and Massachusetts General Hospital (PI Daniel Haber). All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000822

• Extracorporeal Life Support Survival in a Pediatric Hematopoietic Cellular Transplant Recipient with Presumed Graft Versus Host Disease-Related Fulminant Myocarditis

  We report the case of a 15-year-old female with hypodiploid pre-B acute lymphoblastic leukemia status post allogeneic hematopoietic stem cell transplantation (HCT) from a matched unrelated male donor who presented on transplant day +75 with cardiac arrest due to ventricular fibrillation associated with fulminant myocarditis. Using conventional diagnostics, an exhaustive search for microbial pathogens in the heart biopsy as well as nasopharynx, blood, urine, and endotracheal aspirate was performed but did not uncover a candidate pathogen. The family consented to a research study for the use of unbiased next-generation genomic sequencing for pathogen identification in the myocardial biopsy. DNA sequencing was performed on 1.5 x 108 sequencing pairs and no microbial pathogens were identified. Interestingly, a significant component of Y-chromosomal human DNA was identified, suggesting infiltration of at least 10 donor leukocytes per host cell. This finding is grossly consistent with the lymphocyte:myocyte ratio in the biopsy according to visual inspection at 40x magnification. This case merits discussion due to (1) her survival after 17 days of veno-arterial extracorporeal life support (ECLS) and (2) the possibility of cardiotropic graft versus host disease (GVHD).

  Study phs001336

• Whole Exome and Targeted Sequencing in Tourette Syndrome Multiplex Families

  This study consists of 771 individuals from 15 extended, multi-generational Tourette Syndrome (TS) pedigrees collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG), 213 of whom are affected either with TS or its broader, genetically related phenotype, chronic tic disorder (CT). Prior microsatellite linkage analysis, including 624 individuals from these families, has identified a genome-wide significant TS/CT susceptibility locus on chromosome 2p21-24 with two additional loci meeting criteria for suggestive linkage on chromosomes 6p12-21 and 17p11-q11. Subsequent joint linkage and association analysis, incorporating genome-wide SNP genotyping on the Illumina Hap610 platform from 221 individuals, has strengthened the evidence for a major TS/CT locus on chromosome 2p but did not refine the locus further. In addition, haplotype analyses suggest that multiple TS/CT loci may exist on the short arm of chromosome 2. The goal of the current sequencing study is to use exon-focused sequencing, supplemented with targeted sequencing of additional known functional elements on chromosome 2p, to identify susceptibility variants contributing to the highly penetrant TS/CT phenotype in these families.

  Study phs000415

• eMERGE Phase III Clinical Center at Partners HealthCare

  The Partners HealthCare Biobank is a large research data and sample repository working within the framework of Partners Personalized Medicine. It provides researchers access to high quality, consented samples to help foster research, advance understanding of the causes of common diseases, and advance the practice of medicine. The Partners Biobank provides banked samples (plasma, serum and DNA) collected from consented patients. These samples are available for distribution to Partners HealthCare investigators with appropriate approval from the Partners Institutional Review board (IRB). They are linked to clinical data that originates in the Electronic Medical Record (EMR), as well as additional health information collected in a self-reported survey. The Partners Biobank will be genotyping 25,000 subjects with the Illumina Multiethnic Beadchip 1.6 million SNPs with exome and custom content (> 60,000 LoFs). Of the participants genotyped so far, 4929 of 4962 (99.3%) individuals have genotype data that passed the default quality thresholds for the Infinium array (call rate >= 0.99). We are submitting the genotype data to dbGaP for 4929 subjects with 12 phenotypes (based on icd9 codes). We will do annual releases until we reach the full 25,000 genotyped subjects.

  Study phs000944

• CIDR Whole Exome Sequencing in Joubert Syndrome

  The purpose of this study is to identify new genetic causes of neurodevelopmental diseases (NDDs) in the Joubert syndrome (JS) spectrum. Joubert syndrome is a recessive disease characterized by cerebellar vermis hypoplasia. Our currently funded NINDS award entitled "Molecular characterization of Joubert syndrome" seeks to identify new genetic causes through a variety of molecular strategies. Although our previous strategies involved whole genome SNP-scans, followed by candidate gene sequencing to arrive at identification of new JS causes, we have recently moved to Whole Exome Sequencing (WES) as a highly efficient methodology that is optimized for recessive disease. In this pilot project, CIDR has sequenced DNA on probands from 20 inbred families with JS spectrum disorders in which known causes have been excluded, that have not previously undergone genome-wide SNP scans. These paired end reads will be subject to our established bioinformatics pipeline including HOMOZGYOSITY, SNP and INDEL callers in our lab to identify potentially deleterious sequence changes (PDSC). This is followed by analysis to include testing each PDSC for segregation in the whole pedigree, for occurrence in a ethnically-matched cohort, as well as a defined patient cohort patients, in order to validate new NDD genes.

  Study phs000382

• Pharmacogenomic Interactions in Glioblastoma Cell Line Models

  Glioblastoma (GBM) is a lethal disease without effective treatments. To advance toward effective therapeutic approaches that are biomarker-driven, there is a need for new targeted agents and to develop accurate preclinical models that encompass its cellular and molecular diversity. Historical cell line models poorly represent molecular diversity of GBMs, so we developed a living tissue bank encompassing 103 patient-derived GBM cell lines (PDGCLs) as a platform for preclinical pharmacogenomic investigation at scale. Thirty-four PDGCLs were submitted to a comprehensive molecular characterization of copy number alterations and mutations using whole exome sequencing (WES) and gene expression (microarrays), and tested against a panel of 390 small molecules at sixteen different duplicated concentrations. After integrating and systematically correlating molecular alterations with drug sensitivities, we yielded 8,083,140 pharmacogenomic interactions, and discovered novel drug and biomarker combinations which help to prioritize highly effective novel candidate treatments in GBM. Our findings demonstrate the utility of deep characterization of large numbers of models from a single disease to detect complex predictors of compound sensitivity, and indicate novel therapeutic approaches for a large fraction of patients with GBM.

  Study phs001793

• Genomics of Circulating Tumor Cells

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

  Study phs000717

• A Genome-Wide Association Study on Cataract and HDL in the Personalized Medicine Research Project Cohort

  The primary goals of this project are to develop and validate electronic phenotyping algorithms, to accurately identify cases and controls while maintaining a positive predictive value (PPV) of >95%, and to conduct a genome wide association study that advances understanding of two specific yet interrelated disease states, while simultaneously engaging the community in these research efforts. Lipid abnormalities and cataracts are both diseases of public health significance, they share common risk factors, and they are both complex diseases which likely have many genes contributing to disease development. Whole genome association studies with these two outcomes and environmental risk factors could yield novel data about the etiology of the two separate outcomes as well as their interaction. PhenX is a project designed to prioritize Phenotypes and eXposure measures for Genome-wide Association Studies (GWAS). The PhenX Toolkit is a valuable resource for researchers who are planning or expanding a study and would like to incorporate well established measures that have been recommended by experts in the field. We are currently interested in gene-environment interactions for "age related cataract".

  Study phs000170

• Resistance Development in Basal Cell Nevus Syndrome through the Basal to Squamous Transition

  While basal cell carcinomas (BCCs) arise from ectopic hedgehog pathway activation and can be treated with pathway inhibitors, sporadic BCCs display high resistance rates, while tumors arising in Gorlin syndrome patients with germline Patched (PTCH1) mutations are uniformly suppressed by inhibitor therapy. In rare cases, Gorlin syndrome patients on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. Here we report a case of a Smoothened inhibitor (SMOi)-resistant tumor arising in a Gorlin patient on suppressive SMOi for nearly a decade. Using a combination of multi-omics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMOi through the previously described basal to squamous cell carcinoma transition (BST). Intriguingly, through spatial whole exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as novel genetic suppressors of BST resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMOi for not only Gorlin syndrome but sporadic BCCs as well.

  Study phs003415

• Genomic Analysis of Follicular Lymphoma

  We included tumors from newly diagnosed or untreated follicular lymphoma in this study. Samples consented to the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE) were included for data sharing. RNA was extracted from 1) CD19 sorted B cells from tumor cell suspension frozen in dimethyl sulfoxide (DMSO; RNA Tumor B Cell, n=77), 2) tumor cell suspensions frozen in DMSO (RNA Tumor DMSO, n=78), and 3) tumor tissue sections frozen in optimal cutting temperature compound (OCT; RNA Tumor OCT, n=53). For RNA sequencing, library preparation was done using the Illumina TruSeq RNA Exome Kit and sequenced with 100 nucleotide paired-end reads using the HiSeq 4000. DNA was extracted from 1) tumor cell suspensions frozen in DMSO (DNA Tumor DMSO, n=78), 2) tumor tissue sections frozen in OCT (DNA Tumor OCT, n=33), and 3) germline DNA from peripheral blood (n=102) and from normal tissue adjacent tumor (n=9). For whole exome sequencing (WES), library preparation was done using the Agilent SureSelect XT kit and sequenced with 100 nucleotide paired-end reads using the Illumina HiSeq 4000.

  Study phs002989

• Genomic Analysis of Prostate Tumor Heterogeneity in Metastasis

  To investigate the molecular changes, mutations, and signaling pathways that characterize the initial steps of prostate cancer metastasis to the lymph nodes, we analyzed 19 discrete lymph node (LN) metastases, 97 primary tumor foci, 39 benign lymph nodes, and 10 normal adjacent prostate tissue samples from 43 patients enrolled in a clinical trial (NCT01808222) of extended lymphadenectomy and metastasis excision guided by [18F]-fluciclovine PET imaging for high risk, newly diagnosed prostate cancer conducted at Emory University. These patients fell within high or very high-risk groups (T3a, Gleason score 8-10, or PSA greater than 20 ng/ml). Of these patients, 16 had LN metastases at least 4 mm in diameter, and 20 patients had no metastases. For metastatic patients, we performed RNA and Whole Exome Sequencing (WES) on three primary tumor foci, one benign LN, and all LN metastases greater than 4mm in diameter. For non-metastatic patients, we sequenced two primary tumor foci and one benign LN. In total, RNAseq was performed on 165 tissue samples from 43 patients, and WES was performed on 137 samples from 35 patients.

  Study phs003404

• The Somatic Mutational Landscape of Thyroid Cancer in Patients with Germline PTEN Mutations

  PTEN hamartoma tumor syndrome (PHTS) is associated with a high rate of thyroid cancer and benign thyroid disease, yet nothing is known of the genomic landscape of PHTS-associated thyroid tumors. In this study, exome sequencing was performed on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS, sequenced in tumor-normal pairs. Somatic variant calling was utilized to determine the somatic mutational landscape of thyroid tumors in this population. This was then compared to the known mutational landscape of sporadic thyroid cancer in the general population using sequencing data from The Cancer Genome Atlas. The primary finding of the study was that PHTS-associated thyroid tumors had a unique genomic landscape, including a high frequency of second-hit somatic PTEN alterations compared to the sporadic thyroid tumors. Additionally, PHTS-associated thyroid cancers were found to have somatic alterations in BRAF, RAS family members, and genes associated with DNA double stranded break repair. Data available through dbGAP will include tumor BAM files for each tumor, normal BAM files for each patient, and MAF files for PHTS-associated thyroid cancer and PHTS associated benign thyroid nodules.

  Study phs003640

• Adipocytes Regulate Fibroblast Function and Their Loss Contributes to Fibroblast Dysfunction in Inflammatory Diseases

  We profiled live synovial cells from 16 individuals with no diagnosed arthritis using single-cell RNA sequencing. Our study was designed to provide a reference single cell RNA sequencing dataset for researchers interested in studying arthritic synovium, providing sequencing data on healthy synovial cells for comparison to cells from diseased synovial tissues. Synovial tissue was collected post-mortem from three different sources between 2019-2021: the National Disease Research Interchange, a collaboration with Rush University and the Gift of Hope, and the Brigham and Women's Hospital Autopsy Department. To be included in the study, patients had to be between the ages of 18 to 72 and have no diagnosed arthritis or autoimmune diseases. Additionally, this study includes bulk RNA sequencing data of cultured primary synovial fibroblasts isolated from three rheumatoid arthritis patents. Cells were stimulated with either cortisol, fat conditioned media, TGFβ, TNFα, fat conditioned media with mifepristone, TGFβ with fat conditioned media, or TNFα with fat conditioned media. Cells were harvested 4 or 22 hours later and lysates collected for sequencing. Data from this study submitted to the Gene Expression Omnibus (GEO) may be accessed via accession number GSE233504.

  Study phs003304

• Harnessing Epigenetic Regulators to improve HSC-based lentiviral gene therapy

  Curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven for various diseases. However, the low number of true HSCs that can be collected from patients and subsequently in vitro maintenance and expansion of true HSCs for genetic correction remain challenging. Addressing this issue, we here focused on optimizing culture conditions to improve the ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explore the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The HDAC inhibitor Quisinostat and the bromodomain inhibitor CPI203 each promote ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single cell RNA-sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, while addition of Quisinostat or CPI203 improved expansion of HSCs in transduction protocols. Of note, we demonstrated that addition of Quisinostat improved LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effect of epigenetic regulators in hematopoietic stem cell biology and their clinical applications to advance HSC-based gene correction.

  Study EGAS50000000175

• Programs, Origins, and Immunomodulatory Functions of Myeloid Cells in Gliomas

  Gliomas are challenging malignancies characterized by an immunosuppressive microenvironment filled with myeloid cells, whose roles in immune modulation are not fully understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from 85 primary human glioma tumors, related blood samples, and brain tumor organoid models. We found that nearly all glioma-associated myeloid cells express at least one of four distinct immunomodulatory activity programs. These programs include:1. Scavenger Immunosuppressive Program2. Complement Immunosuppressive Program3. Microglial Inflammatory Program4. Systemic Inflammatory ProgramAll four programs are found in both lower-grade and high-grade gliomas and are expressed across various myeloid cell types, whether derived from blood or resident origins. We validated the remarkable plasticity of myeloid cells by showing that the introduction of peripheral blood monocytes into glioma organoid models can induce the emergence of identities resembling microglia, macrophages, and dendritic cells, as well as all four immunomodulatory programs. Our study provides a valuable resource and a new framework for understanding the role of immunomodulatory myeloid cells in gliomas, laying the groundwork for developing effective immunotherapy strategies for glioma patients.

  Study phs003756

• Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. This record includes plasma metabolomics and plasma proteomics data. Genotype data for 3527 CRIC Study partcipants is available at dbGaP in phs000524, "Chronic Renal Insufficiency Cohort (CRIC)-GWAS". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP.More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at the BIBLIOGRAPHY for the Chronic Renal Insufficiency Cohort (CRIC) Study.

  Study phs003709

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

  We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.

  Study phs003406

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• Synovial Fibroblast Gene Expression in Response to Fibronectin Fragment

  Osteoarthritis (OA) is a prevalent joint disease characterized by the progressive degradation of articular cartilage, hypertrophy of neighboring bone, and varying degrees of synovial inflammation. Recent research has highlighted the potential role of synovial fibroblasts in the pathogenesis of OA, particularly their inflammatory properties that disrupt cartilage homeostasis. Notably, degraded cartilage matrix components, such as fibronectin fragments (FN-f), have been identified in the synovial fluid of OA patients, suggesting that FN-f signaling influences the synovium where synovial fibroblasts reside. Despite affecting over 500 million individuals globally, our limited understanding of the underlying mechanisms of OA has significantly impeded the development of effective treatment strategies. To investigate this, we obtained deidentified surgical waste material from individuals undergoing knee replacement for OA. Synovial tissue was used to isolate synovial fibroblasts for cell culture studies. We generated bulk RNA-seq data from primary synovial fibroblasts (N=5 individuals) treated at passage 3 with either Phosphate-Buffered Saline (PBS) as control or FN-f for 18h to model the OA synovial fibroblast phenotype. We identified differentially expressed genes at an adjusted p-value of

  Study phs003999

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

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

  Study phs003235

• Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys

  Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys: cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails a comprehensive epigenetic reprogramming, including Xi reprogramming, yet, as partly observed in vivo, Xa and Xi remain epigenetically asymmetric with incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental-pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.

  Study JGAS000573

• Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer.

  Study: Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer. EudraCT Number: 2014-004417-86 Clinicaltrials.gov Number: NCT02324998 Purpose: Investigate combined PARP and androgen inhibition in primary prostate cancer. Aim: To understand the biological mechanism(s) underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways. Dataset: Single-nuclear RNA sequencing data from post-treatment radical prostatectomy tissue cores for six patients, 3 from each of olaparib and olaparib and degarelix cohorts. Samples were processed for nuclear isolation and extraction, prior to single-nuclear RNA sequencing. 10x libraries were constructed using the 10x supplied protocol, briefly: individual nuclei were trapped into droplets with a single bead, and poly A transcripts were barcoded during reverse transcription. Complementary DNA was amplified, and libraries were prepared for sequencing on NovaSeq 6000 using S4 flow cell (100k reads per cell). FASTQ files were processed using CellRanger pipeline (10X Genomics). Outputs from the CellRanger pipeline were analysed using the Seurat package (v4.9.9.9049) in R (v4.2.0). Processed data is provided as a Seurat object.

  Study EGAS50000000880

• Global Anaplastic Thyroid Cancer Initiative

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

  Study EGAS00001002234