Search Results - EGA European Genome-Phenome Archive

Integrative Single-Cell Analysis of Transcriptome, Epigenome, and Lineage in HIV Latency and Activation

With the development of triple combination antiretroviral therapy, routine HIV treatment eliminates nearly all actively infected cells. Nevertheless, the small reservoir of latently infected cells, which can remain dormant for long periods of time before becoming active and producing new virus particles, represents a crucial barrier to completely curing the disease. Identifying markers that identify latently infected cells or the biochemical factors that control latency activation could enable the effective use of a “shock and kill” strategy, where specific targeting or activation of latently infected cells eliminates the viral reservoir. Our recent work suggests that the global transcriptomic and epigenomic changes during hematopoietic differentiation affect viral latency and activation. Additionally, we recently found that global inhibition of histone deacetylase activity increases viral activation in these cells, further implicating epigenomic changes during activation. These results raise fundamental questions: What are the markers of latently infected cells? How do the transcriptomic and epigenomic states of a cell affect latency and activation? How does the differentiation state relate to viral latency? Here, we leverage our experimental platform for identifying latently and actively infected cells, single-cell transcriptome and epigenome sequencing, and our recently developed computational integration methods to investigate these questions. Our interdisciplinary team combines expertise in HIV basic science, HIV clinical treatment, and bioinformatics to develop an experimental and computational framework for integrated gene expression, chromatin accessibility, and lineage into a single picture of viral latency and activation. Specifically, this project will (1) use single-cell RNA-seq and single-cell ATAC-seq to map the diversity of infected cells, (2) investigate the relationship between hematopoietic differentiation state and viral activation, (3) determine viral integration sites through single-cell RNA-seq, (4) computationally integrate single-cell transcriptome and epigenome profiles, and (5) computationally infer cell lineage relationships among viral genomes and infected cells. To accomplish these goals, we will carry out the following aims: (1) Characterize lineage, transcriptomic and epigenomic diversity of single latently and actively infected primary cells. (2) Investigate latency and activation during in vitro differentiation. (3) Survey single cell diversity of re-activated and in vitro infected cells from cART-suppressed patients. Together, these aims will produce a comprehensive, integrated transcriptomic and epigenomic atlas of the HIV reservoir, identify DNA and RNA biomarkers of latency, and characterize clonal expansion patterns. Our work also develops a broadly applicable experimental and computational framework, laying a foundation for the discovery of novel insights into HIV latency and activation.

Study phs002915

Genetic Testing to Understand and Address Renal Disease Disparities

People of African ancestry (Blacks) have increased risk of kidney failure due to numerous socioeconomic, environmental, and clinical factors. Two variants in the APOL1 gene (GeneID: 8542) are now thought to account for much of the racial disparity associated with hypertensive kidney failure in Blacks. One in 7 AAs carry this risk allele, but it is nearly absent in other populations; the variants protect against infection with African trypanosomiasis which is endemic to Africa. However, this knowledge has not been translated into clinical care to help improve patient outcomes and address disparities. It is unknown whether patient or clinician knowledge of genetic risk impacts patient care (i.e., renal surveillance, BP medication use/intensification) or outcomes such as BP control and CKD. GUARDD is a randomized trial to evaluate the effects and challenges of incorporating genetic risk information into primary care. Hypertensive, nondiabetic, adults with self-reported African ancestry, without kidney dysfunction, are recruited from diverse clinical settings and randomized to undergo APOL1 genetic testing at baseline (intervention) or at one year (waitlist control). Prior to enrolling their patients, providers are educated about genomics and APOL1. Guided by a genetic counselor, trained staff return APOL1 results to patients and provide low-literacy educational materials. Real-time clinical decision support tools alert clinicians of their patients' APOL1 results and associated risk status at the point of care. Our academic - community clinical partnership designed a study to generate information about the impact of genetic risk information on our primary outcome - patient care (renal surveillance by clinicians, of serum creatinine and/or urine albumin tests. with a sub-aim of reduction of systolic blood pressure). Secondary outcomes include impact on primary outcomes at 12 months, psycho-behavioral differences of patients between groups and over time, clinician knowledge, attitudes and beliefs at baseline and 12 months, and differences in outcomes between those tested and not tested. GUARDD will help establish the effective implementation of APOL1 risk informed management of hypertensive patients at high risk of CKD, and will provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices. It will also add to the important dialog about factors that contribute to and may help eliminate racial disparities in kidney disease.

Study phs001620

New England-Based Case-Control Study of Ovarian Cancer

The case-control data provided to dbGaP were collected under NCI grant number CA54419 which had 3 enrollment phases: I (1992-1997), II (1998-2002) and III (2003-2008). Altogether, CA54419 funded 15 years of data and specimen collection, resulting in one of the longest running population based case-control studies of ovarian cancer. The study goal was to examine reproductive factors, lifestyle exposures, and genetic background in relation to ovarian cancer risk. The project recruited cases from Eastern Massachusetts and New Hampshire, and became known as the New England-based Case-Control study (NECC) of ovarian cancer. 3957 ovarian cancer cases diagnosed at ages 18-80 and residing in Eastern Massachusetts and New Hampshire were identified through tumor boards and registries. Of these, 3083 (78%) were eligible and among those eligible, 2203 (71%) were enrolled. After excluding 127 non-epithelial and 35 mixed mesodermal tumors, 2041 cases with epithelial tumors of ovarian, primary peritoneal, and fallopian tube origin, including borderline malignancies were included. On average, cases were interviewed 10 months after their diagnosis. A pathologist reviewed pathology reports and recorded histologic subtype, grade, and stage. Mixed ovarian cancers described as predominantly one type were classified as that type. Undifferentiated, transitional cell tumors, or mixed serous/transitional cell tumors were counted as serous. Other mixed epithelial, malignant Brenner, and unspecified epithelial tumors were classified as other. 2100 controls were identified through random digit dialing (RDD), driver-license lists, and town-resident lists. During the first funding phase from 1992 to 1997, 420 (72%) controls identified through RDD and 102 (51%) through town-resident lists agreed to participate. From 1998 to 2008, only town-resident lists were used to identify potential controls. 4366 controls were identified, of whom 1426 (33%) were ineligible if they had died, moved, or were seriously ill or if they did not have a working telephone, speak English, or have at least one ovary. Of eligible controls, 1362 (46%) declined to participate by phone or via 'opt-out' postcard and 1578 (54%) were enrolled. Controls were frequency matched to cases by 5-year age groups and region of residence. In all phases, after written informed consent, demographic information, reproductive and medical history, and habits were assessed by in-person or telephone interview (in a few instances). All of the questions were framed with respect to a reference date defined as 1 year before the diagnosis date for women in the case group and the date of interview for those in the control group. This study was approved by institutional review boards at Dana Farber Harvard Cancer Center and Dartmouth Medical Center.

Study phs001034

NIPT samples for systematic evaluation of NIPT aneuploidy detection software tools

This dataset contains two sets of samples. The reference sample set consists of a total of 669 samples that had been reported previously to be euploid by the NIPTIFY screening test. The validation sample set is based on a previously published validation study by Zilina et al. (1), consisting of 423 samples, of which 259 were high-risk pregnancies that had undergone diagnostic invasive prenatal analysis (1). All samples were sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously (1). This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#315/T-13). 1. Zilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing non‐invasive prenatal testing in the Estonian public health setting. Prenat Diagn [Internet]. 2019 Dec 6;39(13):1262-8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pd.5578

Dataset EGAD00001007712

NIDA Genetic Epidemiology of Opioid Dependence in Bulgaria (GEODB)

The study was conducted in Bulgaria as a collaboration between the Molecular Medicine Center (Medical University, Sofia), the Bulgarian Addictions Institute (Sofia), the Initiative for Health Foundation (Sofia) and Washington University School of Medicine (Saint Louis, MO, USA). This is a case-population control study. Participants (N=2,499 interviews; N=1,995 with GWAS data) in our study are primarily active heroin users (78%) aged 18 and over, with a median 8.9 years of daily heroin use (minimum of 12 months). Virtually all participants (99.1%) qualified for a lifetime DSM-IV diagnosis of dependence, symptom endorsement probabilities ranging from 77% to 99.3%; and 61% endorsing all symptoms. 85% were heroin injectors and 97% reported using (or having used) heroin daily. Anonymized, population-representative control samples (no phenotypic data, N = 1,062 with GWAS data) were drawn from the MMC repository. Unlike other studies, where samples are clinically ascertained (e.g., from ORT programs), our participants are primarily untreated. PTSD, major depression, suicidality, mania, alcohol, nicotine and substance dependence (separating heroin and opioids) were assessed using the MAGIC (Todd et al., 2003, PMID: 14627881), a broad semi-structured psychiatric assessment tool with good reliability and prospective stability. The onset of (any) illicit drug use in this sample is not particularly remarkable (age~16), but the age of onset of heroin use is much lower than in the USA: 25% by age 16; 50% by age 19, with no differences between ethnicities or gender. This is consistent with findings from other studies in Bulgaria. In contrast, in 2008, SAMHSA estimated an average age of 23.4 for new heroin initiates in the USA. Further, progression from first use to regular use appears to be more rapid, with the majority of participants reporting onset of dependence problems within one year of initiation. Another unique aspect of this study population are the comparatively low levels of polysubstance use (outside of nicotine and alcohol). This early-use, fast-transition and monosubstance heroin pattern stands in sharp contrast to what is reported in many studies in the Western World. In our study, 47% of Ethnic Bulgarians and 66% of Roma used only opioids, even years after the onset of drug use. 15.4% of Ethnic Bulgarians and 66.2% of Roma reported heroin as the very first illicit drug used. Lifetime, 12.5% of Ethnic Bulgarians and 52.8% of Roma report never having used another illicit drug other than heroin more than five times. While both Roma and Ethnic Bulgarians certainly experiment with other drugs, abuse/dependence rates for these drugs are low in Ethnic Bulgarians (from 8.4% for inhalants to 28% for stimulants) and in the Roma population (from 1.3% for hallucinogens to 11.2% for stimulants).

Study phs001804

Inflammatory Bowel Disease Exome Sequencing Study

The Broad Institute and Massachusetts General Hospital (MGH) are launching a new initiative to perform large-scale exome sequencing in inflammatory bowel disease (Crohn's disease and ulcerative colitis). Given the considerable unmet therapeutic need in inflammatory bowel disease (IBD), the recent emergence of rapid and efficient genome sequencing technologies and the compelling evidence for the role of genetics in these disorders have motivated the founding of a collaborative sequencing effort geared toward the discovery of high-impact genetic variants influencing IBD risk that can serve as guides to future therapeutic development and diagnostic tools. The initiative will be directed by experienced IBD researchers from MGH and the Broad Institute but aims to develop a collaborative exome sequencing network that will partner with researchers worldwide. Two large pilot exome sequencing projects are being launched immediately as part of this initiative based on established genetic study designs that enrich for the discovery of rare, high-impact risk and protective variants. 1) Early-onset pediatric IBD: a major focus of the work will surround full-exome sequencing of the earliest-onset childhood IBD cases. It has long been recognized in many diseases that penetrant genetic risk factors are much more likely to be found in cases with unusually early onset. The Broad Institute has completed more than 50,000 exomes in the past two years; and their technical expertise in generating and processing such sequencing data, along with population genetic variation patterns from these experiments, will provide a foundation for obtaining the best outcome in the interpretation of these cases. Samples with IBD onset before 6 years of age - and in some cases going up to age 10 - collected by IBD researchers around the world are welcomed for inclusion in this study. 2) Adult-onset IBD case-control study: Genetic mapping has provided dramatic insights into IBD pathogenesis in recent years, but a substantial amount of heritability - in particular the role of strong-acting rare mutations - is yet to be elucidated. To deliver those insights, IBD cases with an unusually low burden of known genetic risk factors (particularly emphasizing those with positive family history and/or from isolated or enriched populations) will be contrasted with population controls that have an extremely high burden of known IBD risk factors, enhancing discovery of critical protective variants that may provide the best clues for therapeutic development. This project will also be initiated as an international collaboration, particularly among researchers with sample sets with Immunochip genotyping that will enable the immediate genetic identification of these enriched target populations. This project will be supported by the NHGRI Large-Scale Sequencing Program, with all generated data made publicly available to the research community through standard NIH databases.

Study phs001076

PanCuRx Translational Research Initiative

The goal of the PanCuRx TRI is to seek solutions to the high fatality rate of pancreatic adenocarcinoma (PDAC), the most common type of pancreatic cancer, by generating new knowledge about the genetics and biology of the disease, mechanisms of how tumours grow and tailored treatment options. PDAC is the fourth leading cause of cancer death in Canada and is expected to become the second-leading cause of cancer death within the next decade. The current five-year survival rate of eight per cent is the lowest of all epithelial cancers. There are major clinical challenges to treating the disease, including the fact that PDAC spreads to other parts of the body early so surgical removal of the tumour benefits few patients, that PDAC has proven relatively resistant to systemic therapies such as chemotherapy and that there has been limited benefit from the use of newer molecular targeted agents. The PanCuRx team has created the world’s first resource of tumour-purified PDAC whole genomes; more than 500 PDAC samples, with combined clinical annotation, have been successfully sequenced and analyzed at the Ontario Institute for Cancer research in Toronto. The resulting clinical genomic resource created from this data has led to multiple new findings that have established a framework to better understand PDAC biology and lays the foundation for new genomic approaches to better understanding the disease. The team also launched a clinical trial called COMPASS (Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection: A Prospective Study), which is recruiting patients with advanced PDAC (both locally advanced and metastatic) at The Princess Margaret Cancer Centre (PM) in Toronto. The study uses the molecular results from individual patient tumours to guide selection of better second line treatment on a case-by-case basis. The primary objective of the initial study was to assess the feasibility of collecting tumour materials from patients with advanced PDAC and delivering results within 56 days of biopsy. Having achieved this objective, the trial has expanded to other cancer centres across Canada. Pancreatic cancer is one of the most deadly forms of cancer and outcomes have not improved in four decades. The PanCuRx initiative is providing a better understanding of the disease and actively applying new knowledge to cancer patients through clinical trials. This knowledge will help to improve quality of life and prolong survival for pancreatic cancer patients worldwide.

Study EGAS00001002543

Providing safe access to sensitive human data across borders: Federated EGA becomes a reality

Enabling discovery and access to sensitive data across national boundaries is vital for improving human health. It enables more powerful and efficient research by increasing the volume and diversity of data available for analysis. It allows us to better understand the causes of diseases – cancer, rare diseases, infectious diseases like COVID-19 – and develop new medicines and treatments. Sensitive human omics data are typically generated by research initiatives and shared using specialist repositories which provide services for data submission, discovery, and access. The EGA is one such repository. Established in 2008 at EMBL’s European Bioinformatics Institute (EMBL-EBI) in the UK, since 2012 the EGA (“Central EGA”) has been jointly managed by EMBL-EBI and the Centre for Genomic Regulation (CRG) in Spain. Many countries have emerging personalised medicine programmes which generate data from national initiatives. These programmes are driving a transition in human genomics from being research-driven to receiving funding through healthcare. Data generated in a clinical context are subject to stricter governance than research data and must follow national data protection legislation. To solve these challenges, the Federated EGA provides a network of connected resources to enable transnational discovery of and access to human omics data for research, while also respecting jurisdictional data protection regulations. In this way, the Federated EGA infrastructure supports the goals of European initiatives such as the 1+ Million Genomes initiative (1+MG), the European Health Data Space, and a number of EU-funded 1+MG implementation projects including Beyond 1 Million Genomes. The Federated EGA is made up of “Nodes” – typically nationally funded and operated – which store and manage data locally while allowing global discovery within the Federated EGA network. Since 2016, multiple parallel efforts, supported by ELIXIR and other transnational and national initiatives, have created technical and legal frameworks for establishing the Federated EGA. In 2022, the first five Nodes – Finland, Germany, Norway, Spain, and Sweden – officially joined the Federated EGA by signing Federated EGA Collaboration Agreements with Central EGA. The Finnish FEGA Node is operated by CSC - IT Center for Science and provides data management services according to national laws and the requirements of the EU General Data Protection Regulation (GDPR). These services provide tools and support for the whole life-cycle of sensitive research data from collating to analysis, publication, and authorised re-use. The development of the services has been a joint effort with the other Nordic nodes within NeIC's Tryggve and Heilsa projects, and funded by Finnish Ministry of Education and Culture and projects coordinated by ELIXIR Finland. Read more about Finnish FEGA signing. The German Human Genome-Phenome Archive (GHGA) strives to provide a national infrastructure as well as an ethical and legal framework that balances FAIR omics data usage and data protection needs for Germany. As a Germany-wide consortium funded by the German Research Foundation under the umbrella of the NFDI association, GHGA combines the expertise of 21 universities and research institutions to form a federated national infrastructure. Read more about GHGA signing. The German Human Genome-Phenome Archive (GHGA) strives to provide a national infrastructure as well as an ethical and legal framework that balances FAIR omics data usage and data protection needs for Germany. As a Germany-wide consortium funded by the German Research Foundation under the umbrella of the NFDI association, GHGA combines the expertise of 21 universities and research institutions to form a federated national infrastructure. Read more about GHGA signing. In Norway, a key component of the infrastructure is the services of The Sensitive Data Service (TSD) offered by USIT at University of Oslo. The Federated EGA Norway Node is developed by ELIXIR Norway and operated by the University of Oslo as the responsible legal entity. Core software modules are developed jointly with the other Nordic nodes in the NeIC Tryggve and Heilsa projects. Read more about FEGA Norway signing. The Spanish FEGA (es-FEGA) is a national service for storing sensitive biomedical data in Spain. Supported by the Spanish Institute of Bioinformatics (INB) in collaboration with Central EGA, sensitive research datasets are primarily hosted at the Barcelona Supercomputing Centre facilities. The Swedish Sensitive Data Archive is a secure data archive and sharing platform for sensitive datasets. It was developed by the National Bioinformatics Infrastructure Sweden (NBIS) in collaboration with other Nordic ELIXIR Nodes through the Tryggve and Heilsa projects funded by NeIC and coordinated with Central EGA through ELIXIR. Read more about the Swedish Node signing. The Swedish Sensitive Data Archive is a secure data archive and sharing platform for sensitive datasets. It was developed by the National Bioinformatics Infrastructure Sweden (NBIS) in collaboration with other Nordic ELIXIR Nodes through the Tryggve and Heilsa projects funded by NeIC and coordinated with Central EGA through ELIXIR. Read more about the Swedish Node signing. By providing a solution for secure and efficient management of human omics data, the Federated EGA aims to foster data reuse, enable reproducibility, accelerate biomedical research, and improve human health. Find out more Interested in setting up your own Federated EGA Node? Check out the FEGA Onboarding Knowledge Base for more information. The ELIXIR Federated Human Data Community is a great entry point for anyone interested in learning more about the Federated EGA. You can: Join the ELIXIR Federated Human Data Community mailing list (select “Human Data”) Attend the ELIXIR Federated Human Data Community calls

Blog safe-access-to-sensitive-human-data-federated-ega

PREDICT-HD Huntington Disease Study

The purpose of this project is to make clinical measurements from the PREDICT-HD consortium available through the dbGaP mechanism. The phenotype data will first be converted into a community open standard and subsequently exported to dbGaP for archival and open access distribution of the results of the studies. This will permit members of the scientific community to utilize a permanent resource for investigating the interactions of phenotypes upon an international cohort of early Huntington Disease. In version 2 cut of the data we provided HD CAG repeat lengths for both alleles as well as enrollment age of all participants. We have also generated unique identifiers prospectively compatible with the larger initiative GWAS in Huntington's Disease project (also on DbGaP). As such, the version 1 cut of the data was mainly proof of concept and should be deprecated. Going forward, all updates will add-on to version 2 cut of the data. In version 3 cut of the data, we provided baseline or the first usable MRI T1-weighted imaging analysis subcortical and cortical segmentations and cortical parcellations based on a customized Freesurfer 5.2 pipeline developed at The University of Iowa. The customizations to the standard pipeline were mainly to improve bias field correction and image normalization such that segmentation of gray, white, internal csf, dura and surface CSF are optimized for the Freesurfer pipeline. There are 1111 subjects with results in this data release. In version 4 cut of the data, we provided all longitudinal clinical measurements for all subjects (total of 1476) assessmented or enrolled through the end of 2013. Additionally, we are providing measurements on 39 baseline FDG PET images spatially normalized by SPM5 into MNI space, relative regional metabolic values computed in 120 volumes of interest (VOI) defined in the Automated Anatomical Labeling (AAL) Atlas (Tzourio-Mazoyer et al. 2002), and global metabolic values calculated by SPM standard mean voxel value (within per image fullmean/8 mask). This project is a funded ancillary study of PREDICT-HD. In version 5 cut of the data, we provided the first of many forthcoming results from ancilliary studies of PREDICT-HD. In this data cut, we provide individual subject results derived from structural MRI data. The earliest MRI session for each subject was used. The results summarized represent source based morphometry loading coefficients for 23 components (see: "Patterns of Co-Occurring Gray Matter Concentration Loss across the Huntington Disease Prodrome", Ciarochi et al., 2016, Front Neurol. 2016; 7: 147, Published online 2016 Sep 21. doi: 10.3389/fneur.2016.00147]. In this version 6 cut of the data, we provide a full set of derived data, more than 10,000 raw MRI images, and ancillary study data sets. For sample information please link to: PREDICT-HD Biospecimen Resources

Study phs000222

Capturing the Genetic Diversity of the Himba Population

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

Study phs001995

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