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• DERMATLAS__Leiomyoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007630

• Chromosome Errors in Human Eggs and Natural Fertility

  The overall aim of this project is to investigate chromosome errors in human oocytes as a function of age. We aimed to identify molecular mechanisms underpinning these errors and how they may shape the curve of natural fertility in humans.

  Study phs001922

• Long-read data (PacBio)

  The goal of this project was to perform long-read RNA sequencing (LR-seq, PacBio) in combination with short-read RNA-seq for systematic characterization of the isoform diversity in primary breast tumor samples. We sequenced the full-length transcriptomes of 26 breast tumors and 4 normal breast samples.

  Dataset EGAD00001006597

• RB Loss in Resistant EGFR Mutant Lung Adenocarcinomas that Transform to Small Cell Lung Cancer

  Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

  Study EGAS00001001102

• Tumor inflammation and mutational burden are differentially associated with response to nivolumab or nivolumab plus ipilimumab in metastatic colorectal cancer

  Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Exploratory biomarker analyses of tumor and microbiome samples from CheckMate 142 were performed to evaluate associations between various biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures was associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden and degrees of microsatellite instability were associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

  Study EGAS50000000416

• Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression

  Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects from a 10-year prospective study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as subclonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of genetic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

  Study EGAS00001007067

• Combination_Immune_Checkpoint_Inhibition_in_Australian_Rare_Cancers_WES

  Combination immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across tumour types. Rare cancer patients have limited treatment options due to the scarcity of studies of novel treatment options, so they are often offered chemotherapies untested in their disease. ONJ2016-001/CA209-538 is a prospective, multicentre clinical trial of combination ICI (ipilimumab and nivolumab) in patients with advanced rare cancers, including biliary tract, adrenocortical, rare gynaecological and neuroendocrine cancers (https://clinicaltrials.gov/ct2/show/NCT02923934). The primary endpoint is clinical benefit rate (complete response + partial response + stable disease >3 months) by RECIST 1.1. This study involves generation and analysis of pre-treatment formalin fixed paraffin embedded (FFPE) tumour DNA sequencing data, paired with germline DNA sequencing data, to potentially identify genomic biomarkers that may associate with clinical benefit or other clinical efficacy / toxicity metrics.

  Study EGAS00001005709

• Multiple Myeloma Genomic Study (MMGS)

  Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow (BM) infiltration and lytic bone lesions. Recent studies of massive parallel sequencing of tumor cells obtained from the BM of patients with MM have demonstrated significant clonal heterogeneity in MM. Despite this remarkable clonal heterogeneity, it could be envisioned that such clonal diversity may be even higher since single BM samples only represent a small fraction of the whole BM compartment, and the pattern of BM infiltration in MM is typically patchy. In addition, BM biopsies are painful and cannot be repeated multiple times during the course of therapy, indicating a need for less invasive methods to molecularly characterize MM patients and monitor disease progression during the therapy. Thus, optimal characterization of circulating tumor cells (CTCs) may represent a non-invasive method to capture relevant mutations present in PC clones. In addition, MM almost always progresses from precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) to overt MM. However, some patients rapidly progress from MGUS/SMM to overt MM (progressors) with a rate of progression of up to 70% over 5 years, while others remain indolent with minimal progression over the same time period (non-progressors). Although many patients are diagnosed with earlier phases of disease, most patients do not receive treatment until their disease progresses, at which time they have overt end-organ damage. This concept of initiating therapy at the time of symptomatic disease is analogous to initiating therapy in patients with solid tumors only after the development of measurable metastatic disease. It is therefore not surprising that cure is not achieved for most patients with MM. Interestingly, studies have demonstrated that MGUS/SMM clones may already harbor chromosomal alterations (Ig loci or hyperdiploidy) and that progression to MM is mainly due to expansion of clones that were already present in the early stages of MGUS/SMM. However, the biological factors that discriminate progressors from non-progressors in MGUS/SMM are not well known. Therefore, our overarching hypothesis is that an effective therapeutic intervention will result from defining genomic and transcriptomic markers that are associated with disease progression. We believe, therefore, that focused research studies that define molecular mechanisms of clonal evolution in MGUS/SMM/MM will identify novel biomarkers of disease progression and help develop therapeutic agents that prevent or delay progression from MGUS to overt MM. Indeed, by eradicating the disease at the precursor stages, MM may become a preventable disease. Recently, a new term called Clonal Hematopoiesis of Indeterminate Potential (CHIP) has been proposed to describe asymptomatic individuals with hematologic malignancy-associated somatic mutations. Those individuals do not fulfill any diagnostic criteria for any hematological malignancy yet they have a tendency to progress into myelodysplastic syndrome (MDS) or myeloid or lymphoid neoplasia at a rate of around 0.5-1% per year, similar to MGUS. The frequency of CHIP and role of HSCs mutations in enhancing acquisition of somatic mutations in MM plasma cells, allowing progression following treatment, has not been studied. Investigating the dysregulated pathways in early progenitor cells would allow us to understand the reasons of progression and establish novel therapeutic and potentially preventive strategies. This study dissects genomic and transcriptomic characteristics of clonal evolution from MGUS/SMM to MM as well as the characteristics of the tumor microenvironment/immune cells/peripheral blood. Our hypothesis is that molecular biomarkers will be strong predictors of progression from MGUS/SMM to MM and will allow for the development of novel therapeutic agents that prevent or delay this progression. We aim to define genomic and transcriptomic markers that lead to progression from MGUS/SMM to MM in tumor cells, blood biopsies (cell free DNA and circulating tumor cells), and the tumor microenvironment.

  Study phs001323

• Ovarian cancer organoid biobank

  Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a novel protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing the spectrum of ovarian neoplasms, including non-malignant borderline tumors, as well as mucinous, clear-cell, endometrioid, low- and high-grade serous carcinomas. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and inter-patient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

  Study EGAS00001003073

• Genome-Wide Association Study of Relapse of Childhood Acute Lymphoblastic Leukemia

  Using risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the last 40 years. However, a substantial portion of patients experience relapse, many of whom have no known risk factors. Taking a genome-wide approach, we sought to evaluate the relationships between germline SNP genotypes and the risk of relapse in 2,535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We examine prognostic value of selected SNPs in the context of known relapse risk factors (molecular subtypes, minimal residual disease, age and leukocyte count at diagnosis). Associations of relapse-related SNPs with pharmacokinetic and pharmacodynamics of antileukemic drugs offer plausible mechanism by which they are linked to treatment outcome. Finally, we aim to identify SNPs that are related to both genetic ancestry and relapse which are likely to contribute to racial disparities in ALL survival.

  Study phs000638

• Multi-omics analysis of primary glioblastoma cell-lines shows recapitulation of pivotal molecular features of parental tumors

  Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTeX project (GBM and experimental therapeutics), a GBM-patient derived cell line library (GBM-PDCL). Multi-OMIC approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors.

  Study EGAS00001001871

• Coronary Artery Risk Development in Young Adults (CARDIA) Study - Gene Environment Association Studies Initiative (GENEVA)

  For the GENEVA CARDIA project, three genotype call sets were generated from a single set of array scans as a consequence of DNA sample quality problems. These call sets are designated "Birdsuite-1", "Birdsuite-2" and "Beaglecall". ("Beaglecall" used both Birdseed and BEAGLECALL calling algorithms.) An analysis-ready genotypic data set is provided in PLINK format for the "Beaglecall" set only, because it performs very well in QC analyses. Only raw CHP and ALLELE_SUMMARY files are provided for the two Birdsuite call sets because they have significant quality issues. Use of the Beaglecall set is highly recommended. Users of the other two call sets should proceed with caution. More details are given in the genotypic QC report. The CARDIA study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective, multi-center investigation of the natural history and etiology of cardiovascular disease in African-Americans and Whites 18-30 years of age at the time of initial examination. The initial examination included 5,115 participants selectively recruited to represent proportionate racial, gender, age, and education groups from 4 communities: Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA. Participants from the Birmingham, Chicago, and Minneapolis centers were recruited from the total community or from selected census tracts. Participants from the Oakland center were randomly recruited from the Kaiser-Permanente health plan membership. From the time of initiation of the study in 1985-1986, five follow-up examinations have been conducted at years 2, 5, 7, 10, 15, and 20. The Year 25 examination is scheduled to begin in 2010. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors associated with variation in longitudinal blood pressure profiles during the critical transition period from young adulthood to early middle-age; and to characterize their interactions with relevant environmental factors, such as body weight profiles. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were performed at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000309

• NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular Phenotypes

  The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties. A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses. Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924). QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325. Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only. For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

  Study phs000924

• Gene Expression Signatures Characterized by Longitudinal Stability and Inter-Individual Variability Delineate Baseline Phenotypic Groups with Distinct Responses to Immune Stimulation

  RNA sequencing (RNAseq) of peripheral blood lymphocytes was used to develop a means to assess immune function in a way that can be used in discovery science and applied to patients individually in clinical settings. The premise is that profiles of RNA present in immune cells is reflective of the combined influence of genetic and environmental variation on immune potential of individuals and that this potential can be tapped to understand human immunity in a variety of biological contexts. CD4+ cells were isolated from fresh whole blood via positive magnetic bead selection and cell lysates were prepared using Qiazol (QIAGEN) and stored at -80ºC for 3 to 8 months. RNA was extracted in batches for cDNA library preparation and RNA-Seq. For this study, we developed standard operating procedures for handling human blood samples and determined: a) the best way to enrich for CD4+ T cells from whole blood and yield high quality RNA, b) the sensitivity of this RNA profiling strategy, and c) the reproducibility of generated immune profiles from healthy subjects. We then developed bioinformatics processes to establish immune response signatures and immune response phenotypes within cohorts of individuals.

  Study phs001512

• Transcriptomic Analysis of Human Hematopoietic Progenitors from Healthy Donors and Bone Marrow Failure Patients

  The purpose of this study was to define transcriptional changes that occur in the rare and heterogeneous bone marrow progenitors that are affected in Shwachman-Diamond Syndrome. Data are reported for four genetically confirmed SDS patients ranging from 11-26 years old, 3 male and 1 female, and four healthy donors ranging from 25-29 years old, 2 male and 2 female. Subjects provided written, informed consent in accordance with the Declaration of Helsinki's Ethical Principles of Medical Research Involving Human Subjects. Single CD34+ cells were purified from fresh bone marrow and cDNA libraries were prepared using the SMARTer Ultra Low RNA Kit (Clontech; pre-2015) or SMART-Seq v4 Ultra Low RNA Kit (Clontech; post-2015). Libraries were sequenced on a HiSeq 2500 Instrument (Illumina, San Diego, CA) to a read depth of ~3 M paired-end, 25 bp reads per single cell. Paired-end reads were mapped to the hg38 human transcriptome (Gencode v24) using STAR v2.4.2a.

  Study phs001845

• METABRIC miRNA landscape

  MicroRNAs (miRNAs) are key players in cancer pathogenesis1. They display differential expression across breast cancer subtypes, and play oncogenic and tumor-suppressive roles2-6. A systematic study of the global miRNA landscape in breast cancer and the factors shaping it has not been undertaken. Here we report the results of profiling miRNA expression in 1,302 breast tumors with detailed clinical annotation and long-term follow-up, and for which matching genomic and mRNA expression data were available7. This provides a comprehensive view of the quantity, distribution and variation of the miRNA population and dissects how much genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture. The key clinical parameters and cellular pathways related to the miRNA landscape are identified, exemplified by context-dependent interaction with cell adhesion and Wnt signaling. Strikingly, in breast cancer miRNAs appear to act as modulators of mRNA-mRNA interactions rather than molecular switches. We demonstrate an important modulatory role for miRNAs in the biology of breast tumors devoid of somatic copy number aberrations, a common subtype where immune response is prominent. Remarkably, prognostic miRNA signatures derived in this subtype are consistently prognostic across several other subtypes and validate in external cohorts. These findings represent a new framework to study the biology of miRNA in human cancer.

  Study EGAS00000000122

• Gene-Environment Interactions (GxE) and Complex Traits

  Functional variants associated with complex traits tend to fall in non-coding regions and affect regulatory mechanisms that are not yet well characterized. Furthermore, it is generally difficult to determine in which tissues and conditions they may have a functional impact. This is because the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by "environmental" factors. We denominate such variants "gene-expression environment-specific quantitative trait nucleotides" GxE-QTNs. Achieving a better understanding of the mechanisms underlying GxE is a critical step in understanding the link between genotype and complex phenotype. It is also crucial to develop computationally efficient and statistically sound methods capable to integrate tissue/condition-specific functional genomics data to predict and validate when a sequence variant is functional. In this study we developed novel experimental and computational approaches to screen, analyze and functionally characterize genetic variants for complex traits modulated by environmental exposures. To identify and characterize genes with GxE, we analyzed allele specific gene expression in a panel of five relevant tissues (e.g. the vascular endothelium for cardiovascular diseases) under 50 controlled environmental conditions (e.g. glucocorticoids treatment, as a proxy for stress exposure). These data should be useful to develop computational tools that integrate different sources of evidence including data collected by ENCODE, RoadMap Epigenome and GTEx projects to functionally annotate GWAS variants. The experimental and computational tools developed by this project have widespread applicability, for example, can be used to tackle the functional basis of complex traits in other environmental contexts (e.g. other types of stress and hormonal levels) and genetic backgrounds. This resource represents the first comprehensive catalog of genetic variants that interact with environmental exposure in determining human complex traits.

  Study phs001176

• GoDARTS T2D-GENES Exome Sequencing Study

  The GoDARTS T2D-GENES exome sequencing study includes 1924 samples, 965 T2D cases and 959 T2D controls, from European ancestry. This cohort is part of a larger exome sequencing effort from the T2D-GENES project and contains the exome sequencing vcf from the GoDARTS samples. The other data generated from the T2D-GENES project can be found in dbGAP. Samples underwent deep exome sequencing, with SNVs and INDEls called according to GATK best practices.

  Dataset EGAD00001004311

• NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular and Physiological Phenotypes - Whole Genome Sequence

  The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties.A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses.Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924).QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325.Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only.For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

  Study phs001325

• Whole genome sequencing of a Grem1 mutant human tumour

  The BMP antagonist Grem1 has been shown to be associated with a rare human polyposis syndrome (HMPS). We have shown that there is a 40KB duplication on chrom 15 found in some patients with HMPS. Traditional serrated adenomas (rare sporadic polyps) share some morphological features with HMPS polyps and it has long been hypothesised that they are the sporadic version of HMPS polyps. We have obtained of one of these lesions and in this project we aim to characterise this tumour.

  Dataset EGAD00001002182

• Genome-Wide Association Studies of Prematurity and Its Complications

  Preterm labor resulting in the delivery of a premature child is a complex problem with an enormous impact on individuals, families and society. An estimated 500,000 children are born prematurely in the U.S. each year, and 5 million worldwide die annually of prematurity and its complications. Prematurity is also the single largest contributor to disability-adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, its underlying etiology (or etiologies) remains unknown; the single best predictor for preterm delivery is a previous preterm birth. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. A major challenge in studying genetic factors in prematurity is maternal/uterine factors, fetal/placental factors, or both may influence risk. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort (DNBC) is a well-established, prospective cohort that enrolled women early in pregnancy, prior to any adverse pregnancy outcomes, to minimize bias in data collection and sampling. See details at: http://www.ssi.dk/English. The DNBC followed over 100,000 pregnancies beginning in the first trimester and has extensive biological material and epidemiologic data on health outcomes in both mother and child. The current study posted on dbGaP contains data from a genome-wide case/control study using approximately 1,000 preterm mother-child pairs from the DNBC most with spontaneous onset of labor or preterm premature rupture of membranes (PPROM), along with 1,000 control pairs where the child was born at ~40 weeks' gestation. After data cleaning some small changes in case/control status and other variables resulted in minor changes in numbers of cases or controls in certain categories. Environmental variables are being used as covariates in the analysis. To replicate positive findings, we are using additional mother-child pairs from the DNBC and from the general Danish population, as well as 2200 samples coming primarily from an African-American population known to have high rates of preterm labor and delivery. This group includes over 1000 mostly very low birthweight infants, over 500 infant term controls, 326 term mother/baby pairs and 180 preterm mother/baby pairs. The data from these additional cohorts will be available in separate dbGaP postings. The study is expected to yield a better understanding of the biology of parturition, identify common genetic factors that play a role in preterm birth and its complications and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prematurity and its complications through large-scale genome-wide association studies of a well-characterized cohort of Danish mothers and babies. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000103

• Discovery and Characterization of Genetic Risk Loci in Sjogren's Syndrome

  The Sjögren's Genetics Network (SGENE) is an international collaboration focused on identifying and understanding the genetic variations that influence Sjögren’s pathology. Collectively, SGENE collaborators from 26 different sites (5 in the United States; 21 in foreign countries) have recruited a large cohort of geographically diverse participants of European ancestry. Recruitment, sample collection, and genotyping were performed at unique SGENE sites in compliance with local institutional review board approval. High-density SNP genotyping data were collated by the Oklahoma Medical Research Foundation (OMRF) and used to perform a GWAS of Sjögren's of European ancestry. Participants underwent extensive medical assessment for Sjögren's Syndrome using internationally accepted American-European Consensus Group (AECG) classification criteria or the American College of Rheumatology/European League Against Rheumatism classification criteria. Data quality control, GWAS imputation using the Haplotype Reference Consortium, panel version 1.1, and dbGaP preparation/posting were performed at the OMRF. To facilitate research focused on understanding the genetics of Sjögren's syndrome, the Genomic Summary Results from this GWAS are being made available herein using a total of n=3232 Sjögren's cases and n=17,481 controls. A total of n=8962 controls were obtained from our SGENE collaborators or from our previous study (Lessard, et al. Nature Genetics 2013. PMID: 24097067). To achieve adequate case-to-control ratios for the GWAS analyses, population-based control GWAS data were also obtained from dbGaP (phs000428.v2.p2; phs000672.v1.p1; phs000196.v3.p1; phs000187.v1.p1). In accordance with IRB approval, subject consents, and data sharing restrictions, we are also making available the individual-level genotyping data for a subset of Sjögren's cases (n=1,199) that were genotyped at the OMRF.

  Study phs002723

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• NEI CIDR Methylation Profiling of Primary Open Angle Glaucoma in NEIGHBOR Samples

  This is a case-control study of Primary Open Angle Glaucoma (POAG). POAG is a progressive optic neuropathy that eventually leads to blindness. More than 30 million people worldwide have Primary Open Angle Glaucoma (POAG), of which greater than 3 million are blind. Gene expression changes in the retina have been observed for POAG. Several recent studies, including the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) have used GWAS to identify correlative regions of the genome. Despite this, the genetic basis of Glaucoma is not well understood. Epigenetic variation may account for low heritability and environmental effects on human disease. Despite the significant advances being made in understanding the role of epigenetics in gene regulation in other fields, little is known about the relationship between DNA methylation patterns, retinal gene expression, and retinal disease. The goal of this study is to identify differentially methylated regions in the peripheral blood of patients with POAG. The case identification is as per the NEIGHBOR description: Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. POAG and control samples come from two sources: Duke University and Massachusetts Eye and Ear Infirmary (MEEI). These samples were collected and genotyped as part of the NEIGHBOR study. From the 219 POAG cases contributed to NEIGHBOR by Duke, 75 samples were selected for exome sequencing by Dr. Terry Gaasterland (UCSD) as part of an ARRA grant. These samples were selected to mirror the distribution of the entire set of Duke patients for variables such as age, cup-to-disc ratio, CCT, and IOP. From these 75 patients, 43 were selected for our study and an additional seven patients chosen at random, for a total 50 patients from Duke. From the 219 Duke controls, 50 were selected to match the age (at the time of blood draw) and sex of the 50 Duke POAG patients. From the NEIGHBOR control samples from MEEI, 27 were selected who best matched the age (at blood draw), time since sample collection and sex of the POAG probands from GLAUGEN. Additional individual-level phenotype and genotype data may be obtained through the authorized access portal of phs000238 (Neighbor - Glaucoma GWAS Study).

  Study phs000458

• Sequencing of pancreatic cancer primary tumors and metastases

  The extent of heterogeneity of driver gene mutations present in naturally occurring metastases is largely unknown, i.e. treatment-naïve metastatic disease. To address this issue, 60x whole genome sequencing of 26 metastases from 4 patients was carried out. We found that the identical driver gene mutations were present in every metastatic lesion of each patient studied. Passenger gene mutations not known or predicted to have functional consequences accounted for all intratumoral heterogeneity. Even with respect to these passenger gene mutations, the genetic similarity among the founding cells of metastases was markedly higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of driver gene mutations among metastases in the same patient has critical, encouraging implications for the success of future targeted therapies in advanced stage disease.

  Study EGAS00001002186

• Privacy Notice for Data Access Committee Account

  Privacy Notice for EGA Data Access Committee Account This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by Mallory Freeberg, by: email at mfreeberg@ebi.ac.uk , orpost at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: email at dpo@embl.org, orpost at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, orpost at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eupost at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from you: NameEmail addressTitle/PositionOrganisationOrganisational affiliationBusiness addressTelephone numberIP addressesDate and time of a visit to the service websiteOperating systemAmount of data transmittedBrowserUsernamePassword The data controller will use your personal data for the following purposes: To provide DAC user account and authenticated access to the service,To publicly publish some information to facilitate scientific research,To better understand the needs of the data subjects and guide future improvements of the service,To create anonymous usage statistics (from number of DACs, datasets per DAC). 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions (for all user account data),The general public via Internet will get access to your name, email address, business address, telephone number and organisation you belong to. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? Data categories ‘name`, `email address`, `telephone number`, `business address`; `organisation’ of the DAC user are published on the Internet. They thus become accessible to recipients in countries outside the European Economic Area. Insofar as the second joint controller may be subject to GDPR, data transfer to and from the first joint controller (EMBL-EBI), is necessary for important reasons of public interest embedded in the aims of EMBL and justified in the Article 9(4) of IP 68 (equivalent to Article 49(1)(d) of GDPR) read in conjunction with EMBL`s 1973 establishing agreement and Article 179(2) of the Treaty on the Functioning of the European Union 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration.Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period.Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-dac

• Next Generation Sequencing platform for targeted Personalized Therapy of Leukemia - Acute myeloid leukemia

  The advent of high-throughput next generation sequencing (NGS) technologies that are revolutionizing genomics and transcriptomics by providing a single base resolution tool for a unified deep analysis of diseases complexity allows a fast and cost-efficient fine-scale assessment of the genetic variability hidden within cohorts of patients affected by the same leukemia. That being so, by potentially highlighting inter-individual differences that may play a role in the differential success of diverse therapeutic interventions, they promise to be crucial for selecting the most appropriate medical treatments. The project aims at the identification of novel prognostic biomarkers for acute myeloid leukemia (AML) and studied the molecular differences between aneuploid and euploid AML.

  Study EGAS00001005464

• Whole_genome_sequencing_of_100_DDD_trios_with_suspected_noncoding_causal_mutations

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

  Study EGAS00001002452

• Immunoprotective mechanisms and microbiota interplay in Salmonella Typhi infection

  Vaccine development against Salmonella enterica serovar Typhi (S. Typhi) requires a better understanding of interaction between human host and the resident microbial consortia in gastrointestinal tract. Healthy adult volunteers received either Ty21a, M01ZH09 or placebo, and underwent challenges with wt S. Typhi. Stool samples were collected at the screening interview (Baseline 1), prior to the first vaccination visit (Baseline 2), during vaccination (Day -28 and -26 for placebo and M01ZH09 groups; Day -32, -30, -28, -26 for Ty21a group), prior to challenge with S. Typhi (Day 0), and after challenge (day 0 12h, day 1, day 3, day 7, and day 10). 16S rRNA and messenger RNA were extracted from stool and sequenced on the Illumina Miseq and HiSeq 2000 platforms, respectively.

  Study phs001521

• Whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes

  We carried out whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes. This study aimed to reveal the selective accumulation of rare variants in the coding and the UTR sequences within the genes of suicide victims. We also analysed the potential effect of STR and CNV variations, as well as the infection of the brain with neurovirulent viruses in this behavioural disorder. As a result, we have identified several candidate genes, among others three calcium channel genes that may potentially contribute to completed suicide. We also explored the potential implication of the TGF-β signalling pathway in the pathogenesis of suicidal behaviour. To our best knowledge, this is the first study that uses whole-exome sequencing for the investigation of suicide.

  Study EGAS00001002818

• Whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes.

  We carried out whole-exome ultra-high throughput sequencing in brain samples of suicide victims who had suffered from major depressive disorder and control subjects who had died from other causes. This study aimed to reveal the selective accumulation of rare variants in the coding and the UTR sequences within the genes of suicide victims. We also analysed the potential effect of STR and CNV variations, as well as the infection of the brain with neurovirulent viruses in this behavioural disorder. As a result, we have identified several candidate genes, among others three calcium channel genes that may potentially contribute to completed suicide. We also explored the potential implication of the TGF-β signalling pathway in the pathogenesis of suicidal behaviour. To our best knowledge, this is the first study that uses whole-exome sequencing for the investigation of suicide.

  Study EGAS00001003081

• Temporal Lobe Epilepsy and Retrotransposons

  Idiopathic (cryptogenic) epilepsy is a common, chronic group of brain disorders, affecting 1-2% of the US population, creating a significant public health problem because of the associated morbidity and mortality. One subtype of this complex group of brain disorders, temporal lobe epilepsy (TLE), is particularly burdensome, because a substantial fraction of patients do not respond to anticonvulsant medications. If the seizure focus can be localized by imaging and/or EEG, the TLE patient often elects to have a partial resection of the affected temporal lobe, because they have daily seizures, despite multiple pharmacotherapy regimens. Although genetic risk is thought to play a role in TLE, identification of common risk alleles has had limited success. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) retrotransposons (RTPs) to an unexpected degree, such that developing neurons may accumulate de novo L1 insertions. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1s will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional de novo L1s occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to become an epileptic focus. This study leveraged CNS tissue (obtained at craniotomy) from patients with intractable TLE, who have undergone a therapeutic partial resection of one temporal lobe. Using fluorescence-assisted cell sorting of temporal lobe neuronal nuclei, followed by high-throughput sequencing and alignment to the reference genome, detection of de novo L1s will be done. In this manner, it is expected that de-novo intragenic L1s, contributing to idiopathic TLE, will be discovered.

  Study phs002067

• Single cell RNAseq data of human neurons, Bouwen et al Nat Comm 2025

  Brain tumor patients often suffer from epilepsy, but the underlying neuronal changes leading to this neurological symptom are not well understood. This study examined the transcriptomic profiles of human cortical neurons collected from brain tumor patients with or without seizures. The goals of the study were to identify the molecular identities of the recorded neurons and confirm that they are layer 2/3 pyramidal neurons rather than neuron-like tumor cells; and to compare the differential gene expression profiles between patients with and without epilepsy. For each patient, cortical neurons were rapidly isolated from surgically resected tissue and prepared using the Smart-seq2 protocol. Samples from 12 patients were sequenced on an Illumina HiSeq 2500 platform to generate their transcriptomic profiles.

  Study EGAS50000001369

• Effect of the Placental Transcriptome on Stunting in a Longitudinal African Cohort

  Mammals with placentas and flowering plants evolved genomic imprinting in nutritive tissues, the placenta and endosperm, respectively. In these tissues, the genomes inherited from the mother and father are in conflict over resource allocation to offspring. In imprinted genes, transcription is repressed on the paternal or the maternal allele, resulting in allele specific expression (ASE). We investigated the variation in ASE of imprinted genes in term human placentas in order to detect loss of imprinting (LOI), which leads to partial expression of the repressed allele. We collected the placental tissue from birth to women in our multigenerational, prospective cohort study in Mali, West Africa. We followed the women from their own infancies, early childhood to adulthood (age 18+ years). Contingent on prior informed consent, we collected placental tissue and umbilical cord tissue. We conducted RNA-Seq of the fetal compartment of the placentas and targeted DNA-Seq of the umbilical cord tissue, which is fetal, and of saliva samples from parents. Our sequencing effort produced two datasets. The first dataset is the whole transcriptome RNA-Seq dataset of 111 biopsies (59 placentas) and genotyping of 96 genes. Birth length, weight, and placental weight for the children associated with this dataset are listed in the phenotype file (DOI: 10.1093/molbev/msz226). The second dataset includes targeted RNA-Seq of 262 samples (251 placentas) and targeted DNA-Seq for 766 genes. The genes were selected because they met any one of the following criteria: (1) imprinted and reported in some studies, (2) highly expressed in placenta, or (3) relevant to diseases of interest in this cohort (https://doi.org/10.1093/g3journal/jkab176). This study provides the first systematic analysis of variation in LOI across genes and individuals in a human population, and should shed light on the hypothesis that the modulation of imprinting is an epigenetic mechanism and plays a role in the regulation of offspring growth.

  Study phs001782

• Convergent evolution towards CD38 biallelic loss is a recurrent mechanism of resistance to anti-CD38 antibodies in multiple myeloma.

  Monoclonal antibodies directed against CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients will still experience disease relapse. Despite their ubiquity, little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape, whereby tumor cells alter expression of cell surface immunotherapy targets, has been proposed as a potential avenue, and has been seen with other immunotherapies in MM. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, by using whole genome and whole exome sequencing data from 701 newly diagnosed patients, 72 patients at relapse with naivety to anti-CD38 antibodies, and 52 patients collected at relapse following anti-CD38 antibodies, we report biallelic inactivation of CD38 as a recurrent mechanism of resistance in 6% of patients, often via convergent evolution where distinct subclones are advantaged towards the same selective endpoint within the same patient. Monoallelic loss of the CD38 locus was seen in another 14% post-CD38-directed therapy. Three of the cases with biallelic events on CD38 presented with missense mutations and retained CD38 expression. Functional work demonstrated that two of these mutations decreased binding affinity and antibody-dependent cellular cytotoxicity of commercial antibodies Daratumumab and Isatuximab. However, the third mutation (R140G) provided relative resistance only towards one commercial product. Given that patients are often rechallenged with CD38 antibodies following disease progression, these data support the need for next generation sequencing to guide treatment selection.

  Study EGAS50000000709

• H3Africa - Genomic Characterization and Surveillance of Microbial Threats in West Africa

  Viral diseases are remarkably heterogeneous in their presentation and clinical course. Although diseases such as Lassa Fever and Ebola Virus Disease are thought to be severe and rapidly fatal, they can often present with mild symptoms or remain asymptomatic. Host genetic variability is likely an important mediator of this heterogeneity. Complete characterization of the clinical, laboratory, and host genetic features of these illnesses is not only imperative to rapid diagnosis and effective clinical care, but also important for further scientific study. In this project, we propose to address this need through deep characterization of the clinical and laboratory features of viral disease and through study of genetic mediators of resistance to Lassa Fever and Ebola Virus Disease. Will carry out deep clinical characterization and laboratory assessment of viral febrile cases at two West African Collaborative Centers, and will use this data to develop prognostic models using cutting-edge tools in exploratory data visualization and machine learning. Investigate host genetic factors of Lassa Fever and Ebola Virus Disease through genome-wide association studies. We will then develop field-deployable genotyping assays for the top-associated variants, and apply them in new cohorts to replicate our findings and investigate patterns of genetic resistance in clinical subgroups. This project can shed light on the clinical manifestations of viral illness and their host genetic mediators, leading to potential new insights in disease biology and pathophysiology. We will also create a rich resource of clinical, laboratory, and genetic data for these illnesses in two countries in West Africa, which will serve as a foundation for advancing the clinical care and scientific study of viral disease in the region.

  Study EGAS00001007250

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

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

  Dataset EGAD00001009704

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

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

  Dataset EGAD00001008788

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

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

  Dataset EGAD00001008908

• Clinical utility of combined low-pass whole genome and targeted sequencing in liquid biopsies for diagnosis and monitoring of pediatric solid tumors

  Low-pass whole genome sequencing samples from pediatric solid tumor patients who are deceased

  Dataset EGAD00001009972

• Immune profiling reveals enrichment of distinct immune signatures in high-risk oral potentially malignant disorders

  Oral epithelial dysplasia (OED) associates with an increased risk of oral squamous cell carcinoma (OSCC). Changes in the immune landscape of OED that accompany transformation remain understudied. We evaluated gene co-expression in benign lesions (fibroepithelial polyps; FEP), high-risk OED (mod-sev OED) and early stage OSCC. We demonstrate that transcripts indicating immune responses are enriched in high-risk OED. In particular, immune signatures representing high lymphocyte infiltration and cytotoxic responses are prominent, indicating active immunosurveillance. Expression of immune checkpoint molecules was enriched in high-risk OED and further increased in early stage OSCC. Seventy percent of high-risk OED displayed a T cell-inflamed phenotype histology suggesting that they might be responsive to anti-PD-1 immunoprevention. Other immunoprevention strategies are required for the 30% of high-risk OED are not immune-enriched. Overall, our data point the way for new approaches to non-surgical management of OED.

  Study EGAS00001005520

• Epigenome analysis of human trophoblast stem cells

  Trophoblast cells play an essential role in the interactions between the fetus and mother. Mouse trophoblast stem (TS) cells have been derived and used as the best in vitro model for molecular and functional analysis of mouse trophoblast lineages. However, attempts to derive human TS cells have so far been unsuccessful. In this study, we derived human TS cells from human blastocysts. Epigenome analysis revealed that the human TS cells maintained epigenome profiles similar to those of primary trophoblast cells. JGA submission accessions: JGA000122,JGA00000000122

  Study JGAS000112

• A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on NCIC CTG Trial MA.27 Evaluating Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine.

  Source of Patients The source of the patients for this genome-wide case control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma and DCIS in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been ER and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. Case Definition for Musculoskeletal Adverse Events Cases were defined to have had at least one of the following six MSAE): 1. pain - joint, 2. pain - muscle, 3. pain - bone, 4. arthritis, 5. joint - function, 6. musculoskeletal - other. Cases were required to have at least grade 3 toxicity, according to the NCI Common Terminology Criteria for Adverse Events v3.0, or go off treatment for any grade of the six MSAEs; and were required to have had an MSAE within the first two years (i.e., a MSAE occurring after 2 years was not be considered a case). Subjects were excluded from the case group who met the case definition while on celecoxib or in the three months after stopping celecoxib but subjects were allowed to be cases if they developed their first MSAE more than three months after stopping celecoxib. Study Design The design was a nested matched case-control study with two controls selected for each case. Random matching from the potential control group (i.e., risk-set sampling such that controls had at least the same length of followup as the timing of the case event) was done by matching the case on the following factors: 1. treatment arm (exemestane vs. anastrozole, blinded), 2. prior adjuvant chemotherapy (yes vs. no), 3. age at start of treatment (+/- 5 years), 4. Celecoxib allocation (yes vs. no). Attempts were made to exactly match each case with two controls according to the above criteria. If, however, controls could not be exactly matched, "close" matching was used to define a distance between each case and all potential controls in an optimal matching algorithm. Race is a potential confounding factor, and 94% of the MA.27 population is Caucasian, 3% are Black, 1% Asian, 1% American Indian, and 1% are of unknown race. Because there are so few non-Caucasian participants, was restricted to only Caucasians. Following identification of cases and controls, the list was sent to the CALGB Pathology Coordinating Office (PCO) at Ohio State University Medical Center for plating of the samples. Other patient factors that might influence the association of SNP genotypes with a MSAE, either as confounding factors or as effect modifiers, were included as investigational covariates. These include 1. body mass index (BMI), 2. bisphosphonate use, 3. fractures in past 10 years, 4. baseline ECOG performance status, 5. prior hormone replacement therapy, 6. prior adjuvant radiotherapy, and 7. prior taxane treatment. An Honest Broker Process was utilized to ensure patient confidentiality. Genotype Assays and Quality Control A GWAS was performed with the Illumina Human610-Quad at the RIKEN Center for Genomic Medicine. The DNA for all of the samples were adjusted to a concentration of 50 to 100 ng/µL in a final volume of 50 µL. The 96-well plates were designed to have a unique distribution pattern with x duplicates per plate to evaluate genotype concordance. Samples with <98% call rate were removed from analyses. SNPs with ambiguous call will be excluded using the following criteria: 1. low signal intensity of each allele, 2. low cluster separation score, 3. SNP call rate <0.98, 4. SNPs with Hardy Weinberg Equilibrium p-value <0.001 were excluded. X-chromosome SNPs were used to validate female sex and quality control measures were examined across the different submitting centers. For all pairs of subjects, the percentage of matching genotypes were computed to screen for unexpected duplicate samples. All SNPs found to be associated with MSAE were subjected to visual inspection of the cluster plots to verify that the genotype clustering was adequate.

  Study phs000210

• Partially methylated domains across multiple cell types

  Partially methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level. They cover gene poor and transcriptionally inactive regions and tend to be heterochromatic. We present a comprehensive comparative analysis of partially methylated domains in human and mouse cells, to identify structural and functional features associated with them.

  Study EGAS00001003157

• Small variants in mtDNA Canary Islands - WES Illumina (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005678

• Small variants in mtDNA Canary Islands - WGS Illumina (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005679

• Small variants in mtDNA Canary Islands - WGS Oxford Nanopore Technologies (ITER)

  The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. Besides, because of its relevance, we also assess the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short- read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.

  Study EGAS00001005677

• HELIUS cohort

  The gut microbiota composition is unique to every individual but is shaped by common factors including diet, lifestyle, medication use, early-life determinants, living environment or genetics. Most of these factors may be influenced by ethnicity. This study explored variations in fecal microbiota composition in 6048 individuals with different ethnic backgrounds living in the same geographical area (Amsterdam, the Netherlands). The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Study EGAS00001002969

• Stanford Acute Myeloid Leukemia Single-Cell DNA Sequencing

  These are single-cell DNA sequencing data from acute myeloid leukemia samples from Stanford University. They were used in multiple publications to understand clonal evolution in AML.

  Study phs003853

• Genetic_Heterogeneity_of_the_familial_gastric_neuroendocrine_tumors

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002273

• GOSH_Childhood_Leukemia_Behjati_WellcomeCore_RNA

  Paediatric single-cell archival project This project is taking sequential samples of children with B-cell acute lymphoblastic leukaemia (B-ALL) treated at Great Ormond Street Hospital (GOSH) between 2011 and the present day. Patients selected, are those that have done badly (e.g. had to escalate treatment, relapsed or died) despite having apparently ""good"" or ""intermediate"" risk cytogenetics, and often also had immunotherapy (e.g., the bi-specific T-cell engager blinatumomab) because of this. Using samples from key treatment-points, we hope to better characterise their disease and treatment response, to re-define understandings of risk for patients who did unexpectedly poorly. Additionally, we hope to define the disease/immunological factors that determine response to increasingly used immunotherapies within the field of paediatric B-ALL. Each of the samples will be viably frozen bone marrow-derived mononuclear cells. They will come in Eppendorf's, frozen and de-anonymised, from GOSH. We plan to primarily do single cell analysis (GEX, BCR +/-TCR), and then tumour-only WGS and bulk-RNA expression on left-over

  Study EGAS00001007616

• Spatial and temporal genomic evolution in glioblastoma

  Tumor heterogeneity is a challenging barrier to successful targeted therapy in glioblastoma. Identifying the mechanisms that drive cancer cells as they genetically evolve and adapt in response to treatment is a vital goal of modern cancer research. Analysis of sequencing data provides a method for uncovering the mechanisms sustaining tumor heterogeneity and driving evolution. Here, we analyzed genomic profiles of GBM biopsies taken from pre- and post-treatment GBMs (with matched germline controls), to understand 1) the intratumoral clonal compositions of primary GBM and 2) how GBM responds to therapeutic intervention. Our results provide a molecular portrait of GBM recurrence.

  Study EGAS00001001033

• Genomics Define Malignant Transformation in Myeloma Precursor Conditions

  Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

  Dataset EGAD00001015768

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas1. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients2. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Study EGAS00001004544

• Lothian Birth Cohort 1921 whole genome sequencing study

  297 members of the Lothian Birth Cohort 1921 (LBC1921) were sequenced using the Illumina HiSeq X platform. The LBC1921 are a relatively healthy cohort of 550 individuals who underwent cognitive and medical testing at a mean age of 79.1 (SD=0.6) years. They have since undergone four further waves of testing, approximately three years apart.

  Study EGAS00001003818

• Lothian Birth Cohort 1936 whole genome sequencing study

  1075 members of the Lothian Birth Cohort 1936 (LBC1936) were sequenced using the Illumina HiSeq X platform. The LBC1936 are a relatively healthy cohort of 1091 individuals who underwent cognitive and medical testing at a mean age of 69.5 (SD=0.8) years. They have since undergone four further waves of testing, approximately three years apart.

  Study EGAS00001003819

• Heart Failure Network: Diuretic Optimization Strategies Evaluation in Acute Heart Failure (HFN DOSE-BioLINCC)

  ObjectivesThe DOSE study sought to evaluate the most effective dosing (high vs. low) and administration (continuous infusion vs. intermittent boluses) combination of the diuretic Furosemide in the treatment of patients with acute decompensated heart failure.BackgroundAcute decompensated heart failure is the most common cause of hospital admissions among patients older than 65 years of age and is responsible for more than 1 million hospitalizations annually in the United States. Intravenous loop diuretics are an essential component of current treatment and are administered to approximately 90% of patients who are hospitalized with heart failure. Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely with regard to both the mode of administration and the dosing.SubjectsA total of 308 patients were enrolled between March 2008 and November 2009 at 26 clinical sites in the United States and Canada. DesignThe DOSE study was a prospective, randomized, double-blind, controlled trial with a 2-by-2 factorial design. Patients were randomly assigned to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion.The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.ConclusionsAmong patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Felker et. al., 2011, PMID: 21366472)

  Study phs003524

• EGA FUSE Client

  EGA FUSE Client What is EGA FUSE Client? The EGA FUSE Client is a Java Native Runtime (JNR) based Filesystem in Userspace (FUSE) client that allows users to access authorised EGA files by presenting them in a virtual directory. This means that users can use authorised EGA files like regular files without having to download them first. The EGA FUSE Client is a useful tool for researchers who need to access and work with large amounts of EGA data. Why use EGA FUSE Client? The EGA FUSE Client provides several benefits for researchers working with EGA data: Efficient use of storage space: With the EGA FUSE Client, users can access authorised EGA files without having to download them first. This means that users can save storage space on their local machines. Faster access to data: Since users can access authorised EGA files directly through the EGA FUSE Client, they can work with the data more quickly than if they had to download the files first. Simplified workflow: The EGA FUSE Client presents authorised EGA files in a virtual directory, allowing users to work with the files like regular files. This simplifies the workflow for researchers who need to access and work with large amounts of EGA data. Get started with EGA FUSE Client To get started with EGA FUSE Client visit the EGA FUSE Client GitHub repository for more information and installation instructions.

  Documentation access/download/visualisation/fuse-client

• Cell-free DNA fragmentation patterns and personalized sequencing reveal circulating tumor DNA in urine and plasma of glioma patients

  Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy as levels in body fluids are low. We determined the glioma-derived DNA fractions in tumor biopsies, in cerebrospinal fluid (CSF), plasma and urine samples, using deep sequencing of personalized capture panels. By sequencing cfDNA across thousands of mutations identified individually in each patient’s matched tumor we detected tumor-derived DNA in plasma (10/12) and urine samples (8/11). The median tumor fraction was 6.4x10-3 in CSF, 3.1x10-5 in plasma and 4.7x10-5 in urine. We identified a shift in the size distribution for mutant cfDNA fragments in these body fluids. Next, we analyzed cfDNA fragment sizes with paired-end shallow whole genome sequencing (WGS) in urine samples from 35 patients with gliomas, 8 individuals with non-malignant brain disorders, and 26 controls (n=69 individuals, 96 samples). cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (t-test, p=1.7x10-2) and compared to urine of controls (t-test, p=5.2x10-9). The proportion of DNA fragments <60 bp was higher in glioma patients urine and could be used for classification (AUC=0.93). Machine learning models integrating fragment lengths could identify urine samples from glioma patients (AUC=0.97 in cross-validation).

  Study EGAS00001004355

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): Large Scale Flu Surveillance Study (LSFS)

  The purpose of this study was to better understand behavioral and physiological functioning in relation to recent self-reported influenza and influenza-like-illness (ILI), including coronavirus disease (COVID-19). Over 65,000 Achievement members responded to a weekly one-click survey asking if they had experienced ILI within the previous 7-day period. If they responded no, they were given the option to complete a survey about their risk factors and behavior. If they responded yes, they were given the option to complete a survey asking about the specifics of the incident. Participants were also asked to sync their wearable activity trackers and health apps in order for researchers to better understand changes in behavioral and physiological outcomes related to self-reported ILI experiences.DOI: https://rapids.ll.mit.edu/10.57895/fkth-d352

  Study phs002539

• Symptom Clusters in Oncology Patients Receiving Chemotherapy

  The parent longitudinal study evaluated the symptom experience of oncology outpatients receiving chemotherapy. Patients completed questionnaires in their homes a total of six times (assessments 1 through 6). The questionnaires were timed to evaluate symptoms associated with the receipt of two cycles of chemotherapy that were administered approximately a month apart. Assessments 1 and 4 evaluated symptoms prior to the receipt of chemotherapy. Assessments 2 and 5 evaluated symptoms in the week following the administration of chemotherapy. Assessments 3 and 6 evaluated symptoms two weeks following the administration of chemotherapy. For this analysis, morning and evening fatigue data from the enrollment assessment (i.e., prior to the second or third cycle of chemotherapy) and the assessment that was done approximately 1 week after administration of chemotherapy were evaluated. Patients completed the Lee Fatigue Scale to obtain information on morning and evening fatigue severity. For the morning fatigue assessment, patients were asked to describe how they “felt over the past week when they woke up in the morning”. For the evening fatigue assessment, they were asked to describe how they felt over the past week “before they went to bed at night”. Medical records were reviewed for disease and treatment information. Epigenome assays (microarray) were completed for 1170 patients. Whole transcriptome sequencing (bulk RNA-Seq) was completed for 651 patients.

  Study phs003863

• Long read transcriptome of DM1 patients whole blood

  DM1 is characterized by dysregulation of alternative mRNA splicing, to an quantitative as well as qualitative extend that is heterogenous between clinically similar patients. Hundreds of transcripts have been identified that can be misspliced in DM1, and for many of these it is still unclear whether they generate stable proteins in DM1 patients. We generated long-read transcriptome data of DM1 patients whole blood after hemoglobin depletion. Each sample is a mix of 5 patients of varying age.

  Study EGAS50000000196

• Genotype calls (vcf files)

  Genotype calls for 83 Aboriginal Australian genomes split by chromosomes. In short, genotypes were called individually with samtools. They were subsequently filtered with thresholds related to sequencing depth, location of variants, sequencing error, and strand bias. Once combined, the genotypes were filtered when not in Hardy-Weinberg equilibrium. The genomes were phased with IMPUTE using the 1000 Genomes reference panel. NB: for the Y chromosomes​, only the 44 Aboriginal Australian males are included.

  Dataset EGAD00001004155

• EGA submission account terms

  Submission account terms Each EGA submission account has a dedicated submission box. To ensure continued service to all submitters EGA submission boxes should not exceed 8Tb in size, and cannot exceed 12Tb. Those that are near to or exceeding this value will be monitored on a weekly basis by the helpdesk team and the submitter will be contacted and guidance provided accordingly on completing their metadata registration. You will be able to register your metadata associated with the files in your submission account via EGA Submitter Portal, Webin or the EGA REST API. EGA also requests that metadata is submitted within 60 days of upload data to a submission box. When we detect files that are over 60 days old in a submission box we will notify the submitter requesting that metadata be submitted or the files removed from the submission box. It is important to note that data is not archived at the EGA until the metadata describing the files has been associated and the archival process has completed. It is only when associated metadata has been submitted that the archival process into EGA is fully triggered. EGA removes files from the submission box once they have been successfully archived, so no action is required by a submitter to remove successfully archived files. Files over 90 days old will be deleted from the submission box unless EGA Helpdesk has been contacted and confirmed an exemption with the submitter.

  Documentation submission/terms

• Congenital_anosmia_2

  Congenital anosmias can be complete (the lack of a sense of smell) or specific (the inability to detect specific smells). Here we obtained genomic DNA from families with multiple individuals with anosmia, suggesting they are congenital. These include those inherited in a manner consistent with dominant and recessive alleles. We have sequenced the exomes of both affected and unaffected family members on the Illumina platform.

  Study EGAS00001001429

• ELLIPSE Prostate Cancer Meta-Analysis and Genotyping

  The ELLIPSE Consortium is an international effort to discover risk loci for prostate cancer. It includes the meta-analysis of existing GWAS data as well as novel GWAS, exome, and iCOGS genotyping. The GWAS meta-analysis includes the following cases and controls from studies of European ancestry: UK GWAS stage 1 (Illumina Infinium HumanHap 550 Array: 1854 cases and 1894 controls), UK GWAS stage 2 (Illumina iSELECT: 3706 cases and 3884 controls), CAPS1 (Affymetrix GeneChip 500K: 474 cases and 482 controls), CAPS2 (Affymetrix GeneChip 5.0K: 1458 cases and 512 controls), BPC3 (Illumina Human610 Illumina: 2068 cases and 3011 controls), PEGASUS (HumanOmni2.5: 4600 cases and 2941 controls). The OMNI 2.5M genotyping was conducted for 977 prostate cancer cases from UKGPCS. The Exome SNP array genotyping was conducted for 4741 subjects from UKGPCS. The iCOGs genotyping was conducted for 10366 subjects which includes the Multiethnic Cohort (n=1648) and UKGPCS (n=8718). Below is a description of each study that contributed to the meta-analysis of men of European ancestry. Information about the studies that contributed to the multiethnic meta-analysis can be found on the associated study page and also in Conti et al (Nature Genetics, PMID:33398198).   UK GWAS Stage 1 (UK1) and Stage 2 (UK2): The UK Genetic Prostate Cancer Study (UKGPCS) was first established in 1993 and is the largest prostate cancer study of its kind in the UK, involving nearly 189 hospitals. We are based at The Institute of Cancer Research in Sutton, Surrey, and collaborate with the Royal Marsden NHS Foundation Trust. Our aim is to find genetic changes which are associated with prostate cancer risk. Our target is to recruit 26,000 gentlemen into the UKGPCS by 2017. Men are eligible to take part if they fit into at least one of the following groups: They have been diagnosed with prostate cancer at 60 years of age or under (up to their 61st birthday). They have been diagnosed with prostate cancer and a first, second or third degree relative where at least one of these men were diagnosed with prostate cancer at 65 years of age or under. They are affected and have 3 or more cases of prostate cancer on one side of their family. They are a prostate cancer patient at the Royal Marsden NHS Foundation Trust. We have to date recruited around 16,000 men on whom we have germline DNA and clinical data at diagnosis. The UK GWAS is based on genotyping of 541,129 SNPs in 1,854 individuals with clinically detected (non-PSA-screened) prostate cancer (cases) and 1,894 controls. 43,671 SNPs showing strong evidence of association in stage 1 were followed up by genotyping a further 3,268 cases and 3,366 controls from UK and Melbourne in stage2. CAPS1 and CAPS2: The CAPS (Cancer of the Prostate in Sweden) study represents a large Swedish population-based cancer study, comprising 3,161 cases and 2,149 controls, recruited between 2001 and 2003. Biopsy confirmed prostate cancer cases were identified and recruited from four out of six regional cancer registries in Sweden, diagnosed between July 2001 and October 2003. Clinical data including TNM stage, Gleason grade and PSA levels at time for diagnosis were retrieved through record linkage to the National Prostate Cancer Registry. Control subjects, who were recruited concurrently with case subjects, were randomly selected from the Swedish Population Registry and matched according to the expected age distribution of cases (groups of 5-year intervals) and geographic region. Whole blood was collected from all individuals for extraction of genomic DNA. A GWAS was conducted in two parts. In the first phase (CAPS1) 498 cases and 502 controls were genotyped, in the second phase 1,483 cases and 519 controls were genotyped. Genotyping was performed using the GeneChip Human Mapping 500K (CAPS1) and 5.0K (CAPS2) Array Set from Affymetrix (Santa Clara, CA). The National Cancer Institute Breast and Prostate Cancer Cohort Consortium, BPC3: BPC3 was a consortium of prospective cohort studies investigating genetic and gene-environmental risk factors for breast and prostate cancer. Each study selected cases and controls for this study as described below. The clinical criteria defining advanced prostate cancer (Gleason = 8 or stage C/D) were either obtained from medical records or cancer registries. The Gleason score source was either surgical specimens (radical prostatectomy or autopsy) or the diagnostic biopsy (needle biopsy or TURP). When multiple Gleason scores were available the surgical value was used. PLCO was removed from the analysis as the samples were included in the Pegasus GWAS described below. In total 2,473 advanced prostate cancer cases and 3,534 controls were included in the analysis following QC. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: ATBC was a randomized, placebo-controlled primary prevention trial to investigate whether α-tocopherol or ß-carotene supplementation reduced the incidence of lung or other cancers in male smokers. Between 1985 and 1988, 29,133 men ages 50 to 69 years were enrolled in the trial from Finland and randomized to supplementation (50 mg α-tocopherol, 20mg ß-carotene, or both) or placebo. Men with a prior history of cancer, other than non-melanoma skin cancer or carcinoma in situ, were excluded from participating. Incident cancer cases are identified through linkage with the Finnish Cancer Registry, which has ~100% ascertainment of cancer cases nationwide. Cases included 249 men diagnosed with advanced prostate cancer (Gleason = 8 or stage C/D) from 1985 to 2003 with DNA available. Controls were 1,271 men selected previously for a GWAS of lung cancer in ATBC without a diagnosis of prostate cancer. CPSII, Cancer Prevention Study II: CPSII is a cohort study started in 1982 to investigate the relationship between dietary, lifestyle and other etiologic factors and cancer mortality. Approximately 1.2 million men and women enrolled in the study from 50 states in the U.S. In 1992, a subset of these participants (n= ~184,000) were enrolled in the CPSII Nutrition Cohort to examine the relationship between dietary and other exposures and cancer incidence. Blood samples were drawn from approximately 39,376 members of the Nutritional Cohort from 1998 to 2001, and buccal cells were collected from 69,467 members from 2001 to 2002. Cancer cases are identified by self-report through follow-up questionnaires followed by verification through medical records and/or linkage to state cancer registries as well as death certificates. A total of 660 advanced prostate cancer cases (Gleason = 8 or stage III/IV) with a source of DNA were identified for this study. Controls were 660 men matched on ethnicity, date of birth, sample collection date and DNA type. EPIC, European Prospective Investigation into Cancer and Nutrition: EPIC is a prospective study designed to investigate both genetic and non-genetic risk factors for different forms of cancer. Study participants were almost all white Europeans. Approximately 500,000 individuals (150,000 men) in EPIC were recruited between 1992 and 2000, from 23 centers in 10 European countries. Overall approximately 400,000 subjects also provided a blood sample at recruitment. The methods of recruitment and details of the study design are described in detail elsewhere. In brief, study participants completed an extensive questionnaire on both dietary and nondietary data at recruitment. The present study includes subjects from advanced prostate cancer cases (Gleason = 8 or stage III/IV) matched to controls based on study center, length of follow-up, age at enrollment (± 6 months), fasting and time of day of blood collection (± 1 hour). The advanced prostate cancer subjects were from 8 of the 10 participating countries: Denmark, Germany, Greece, Italy, the Netherlands, Spain, Sweden and the United Kingdom (UK). France and Norway were not included in the current study because these cohorts only included female subjects. All participants gave written consent for the research and approval for the study was obtained from the ethical review board from all local institutions in the regions where participants had been recruited for the EPIC study. HPFS, Health Professionals Follow-up Study: HPFS began in 1986 and is an ongoing prospective cohort study of 51,529 United States male dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians 40 to 75 years of age. The baseline questionnaire provided information on age, marital status, height and weight, ancestry, medications, smoking history, disease history, physical activity, and diet. At baseline the cohort was 97% white, 2% Asian American, and 1% African American. The median follow-up through 2005 was 10.5 years (range 2-19 years). Self-reported prostate cancer diagnoses were confirmed by obtaining medical and/or pathology records. Prostate cancer deaths are either reported by family members in response to follow-up questionnaires, discovered by the postal system, or the National Death Index. Questionnaires are sent every two years to surviving men to update exposure and medical history. In 1993 and 1994, a blood specimen was collected from 18,018 men without a prior diagnosis of cancer. Prostate cancer cases are matched to controls on birth year (+/-1) and ethnicity. Controls are selected from those who are cancer-free at the time of the case’s diagnosis, and had a prostate-specific antigen test after the date of blood draw.   MEC, Multiethnic Cohort: The Multiethnic Cohort Study is a population-based prospective cohort study that was initiated between 1993 and 1996 and includes subjects from various ethnic groups - African Americans and Latinos primarily from Californian (great Los Angeles area) and Native Hawaiians, Japanese-Americans, and European Americans primarily from Hawaii. State drivers’ license files were the primary sources used to identify study subjects in Hawaii and California. Additionally, in Hawaii, state voter’s registration files were used, and, in California, Health Care Financing Administration (HCFA) files were used to identify additional African American men. All participants (n=215,251) returned a 26-page self-administered baseline questionnaire that obtained general demographic, medical and risk factor information. In the cohort, incident cancer cases are identified annually through cohort linkage to population-based cancer Surveillance, Epidemiology, and End Results (SEER) registries in Hawaii and Los Angeles County as well as to the California State cancer registry. Information on stage and grade of disease are also obtained through the SEER registries. Blood sample collection in the MEC began in 1994 and targeted incident prostate cancer cases and a random sample of study participants to serve as controls for genetic analyses. PHS, Physicians Health Study:PHS was a randomized trial of aspirin and ß carotene for cardiovascular disease and cancer among 22,071 U.S. male physicians ages 40-84 years at randomization; none had a cancer diagnosis at baseline. The original trial ended, but the men are followed. From 1982 to 1984, blood samples were collected from 14,916 physicians before randomization. Participants are sent yearly questionnaires to ascertain endpoints. Whenever a physician reports cancer, we request permission to obtain the medical records, and cancers are confirmed by pathology report. We obtain death certificates and pertinent medical records for all deaths. Follow-up for nonfatal outcomes in PHS is over 97% complete, and for mortality, over 99%. PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial:PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen (PSA) annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 754 men diagnosed with advanced prostate cancer (Gleason = 8 or stage III/IV) from either arm of the trial. Of these cases, 317 were genotyped previously as part of Cancer Genetic Markers of Susceptibility (CGEMS), a GWAS for prostate cancer. Controls included 1,491 men without a diagnosis of prostate cancer from the screening arm of the PLCO trial. All subjects provided informed consent to participate in genetic etiology studies of cancer and other traits. This study was approved by the institutional review boards at the ten centers and the National Cancer Institute. PLCO was removed from the meta-analysis of the BPC3 studies as a consequence of PEGASUS below. PEGASUS, Prostate cancer Genome-wide Association Study of Uncommon Susceptibility loci: Pegasus is a genome-wide association nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. PLCO is a multicenter, randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer. Between 1993 and 2001, over 150,000 men and women ages 55-74 years were recruited from ten centers in the United States (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO; and Washington, D.C.). Men randomized to the screening arm underwent prostate cancer screening with prostate-specific antigen annually for six years and digital rectal exam annually for four years. Blood specimens were collected from participants randomized to the screening arm of the trial, and buccal cell specimens were obtained from participants randomized to the control arm. Cases included 4,598 men of European ancestry diagnosed with prostate cancer from either arm of the trial and controls included 2,941 men of European ancestry without a diagnosis of cancer from the screening arm, matched on age and year of randomization. All subjects provided informed consent, and the study approved by the institutional review board at the National Cancer Institute. Funding:This work was supported by the GAME-ON U19 initiative for prostate cancer (ELLIPSE): U19 CA148537. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233, U01-CA98710, U01-CA98216, and U01-CA98758, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The ATBC study and PEGASUS was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. CAPS: The Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden was supported by the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant: K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant: 09-0677), the Hedlund Foundation, the Söderberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linnér’s Minne, Karlsson’s Fund for urological and surgical research. We thank and acknowledge all of the participants in the Stockholm-1 study. We thank Carin Cavalli-Björkman and Ami Rönnberg Karlsson for their dedicated work in the collection of data. Michael Broms is acknowledged for his skillful work with the databases. KI Biobank is acknowledged for handling the samples and for DNA extraction. Hans Wallinder at Aleris Medilab and Sven Gustafsson at Karolinska University Laboratory are thanked for their good cooperation in providing historical laboratory results. UKGPCS would like to acknowledge the NCRN nurses and Consultants for their work in the UKGPCS study. We thank all the patients who took part in this study. This work was supported by Cancer Research UK (grants: C5047/A7357, C1287/A10118, C1287/A5260, C5047/A3354, C5047/A10692, C16913/A6135 and C16913/A6835). We would also like to thank the following for funding support: Prostate Research Campaign UK (now Prostate Cancer UK), The Institute of Cancer Research and The Everyman Campaign, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The MEC was supported by NIH grants CA63464, CA54281 and CA098758. 

  Study phs001120

• A plasma protein biomarker signature that differentiates acute rheumatic fever from related clinical presentations

  Acute Rheumatic Fever (ARF) is a systemic inflammatory condition triggered by Group A Streptococcus infection, with timely diagnosis critical to prevent Rheumatic Heart Disease. ARF pathogenesis is poorly understood and diagnosis is based on clinical criteria. Here, we compared ARF cases and well-defined controls from two Uganda cohorts. We identified a 5-protein signature that discriminates ARF patients from clinically-similar conditions (receiver operating characteristic-area under the curve (ROC-AUC)=1.0, n=18 definite ARF vs n=9 known alternate diagnosis; ROC-AUC=0.97, n=18 definite ARF vs n=13 unknown alternate diagnosis), which retained very good diagnostic value in a validation cohort (ROC-AUC=0.83 n=26 definite ARF vs n=13 unknown alternate diagnosis). Pathway analysis identified the epithelial-mesenchymal transition pathway as highly-associated with acute ARF, suggesting that tissue damage and repair is central to ARF pathogenesis. Our findings require further validation, yet highlight the potential for proteomics to identify clinically useful diagnostic biomarkers that would revolutionise ARF diagnosis and treatment.

  Study EGAS00001008381

• scMultiome (snRNA + snATAC) data of 26 regionally sampled GBM tissue from 6 patients

  This dataset contains snRNA-seq data of 26 regionally sampled GBM tissue (peritumoral region, tumor edge, and tumor core). Regionally sampled GBM patient tissue was dissociated and nuclei were processed unsorted or by sorting with 7AAD to remove debris and dead cells. Single-nuclei suspension was prepared following the nuclei isolation protocol Single Cell Multiome ATAC + Gene Expression Sequencing protocol using Chromium Nuclei Isolation Kit. Single-nuclei suspension was prepared following the nuclei isolation protocol Single Cell Multiome ATAC + Gene Expression Sequencing protocol using Chromium Nuclei Isolation Kit, nuclei were barcoded and RNA and ATAC libraries were constructed, allowing for simultaneous capture of transcriptome and epigenome from the same cells.

  Dataset EGAD50000001838

• A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

  We generated a single-cell RNA-seq atlas capturing over 100,000 cells spanning all stages of the mouse cerebral development. By examining data from over 100 cerebral tumour samples, our study reveals that, despite the phenotypic/genotypic differences between the tumour types, they are all comprised of developmental sublineages that map most closely to embryonic or juvenile stages of development.

  Study EGAS00001006237

• National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS)

  NIAGADS is an NIH controlled-access data repository that collaborates with researchers around the world to facilitate data access and sharing for genomic and associated omics data related to Alzheimer's Disease (AD), Alzheimer's Disease Related Dementias (ADRD), as well as healthy aging. Serving as the data coordinating center for the Alzheimer's Disease Sequencing Project (ADSP), NIAGADS hosts all ADSP-generated whole-exome, whole-genome and associated phenotypes. Other data types hosted by NIAGADS include genotype SNP arrays, functional omics, fluid biomarkers, aggregated imaging data (such as volumetric data for brain regions of interest), and summary statistics. In adherence with NIH security best practices and genome data sharing policies, NIAGADS supports data access requests through review by an NIH-appointed and registered Data Access Committee. Data stored within NIAGADS cannot be requested via dbGaP. Data requests must go through the NIAGADS Data Sharing Service (DSS) via the following NIAGADS url: https://dss.niagads.org/. Questions related to the request of data should be directed to the NIAGADS admin team at: niagads@pennmedicine.upenn.edu. DSS is a FISMA certified platform built by a team of data scientists at the University of Pennsylvania to support the request and access of AD/ADRD data by qualified researchers internationally. Questions related to the use of data hosted in the DSS should be directed to the Portal admin team at: help@niagads.org.

  Study phs004180

• Biopsy-Derived Organoids in Personalised Early Breast Cancer Care: Challenges of Tumour Purity and Normal Cell Overgrowth Cap Their Practical Utility

  The ability to establish organoids composed exclusively of tumour rather than healthy cells is essential for their implementation into clinical practice. Organoids have in recent years emerged as a powerful tool to expand patient material in culture and generate modifiable 3D models derived from humans or animal models. For translational research, they enable the creation of model systems for an ever-increasing number of cell types and diseases. And in personalised medicine, they potentially allow for functional drug testing with high predictive power in certain settings. We found that using biopsy material from untreated, early-stage primary breast cancer patients poses significant challenges for consistently culturing tumour cells as organoids. Specifically, we observed frequent outgrowth of genetically normal, non-cancerous epithelial cells. We analysed >100 biopsy samples from early-stage breast cancer and present our large collection of >70 organoid lines. We also show methods of assessing successful tumour cell culture in a time and cost-efficient manner, proving a high rate (>85%) of normal cell overgrowth in early-stage breast cancer organoids. Finally, we show a number of successful attempts to culture cancer organoids from mastectomy-derived tissue of advanced, metastatic breast cancer. We conclude that the usefulness of organoids from early breast cancer for translational research and personalised medicine, especially guidance of adjuvant or post-surgical maintenance therapy, is strongly limited by the low success rate of culturing cancerous cells under organoid conditions.

  Study EGAS50000000605

• WGS Fastq files from the CPC-Gene project in support of PRAD-CA, DCC Release 26

  PRAD-CA, DCC Release 26 : This dataset contains fastq files with Whole genome sequencing data for the CPC-Gene Project. Data from each sample was generated using multiple whole genome libraries and sequenced across multiple runs

  Dataset EGAD00001003706

• Integrative Age-Related Changes in Genome and Epigenome in Human Lung in Relation to Smoking

  The Integrative Age-Related Changes in Genome and Epigenome in Human Lung in Relation to Smoking study was designed to assess DNA methylation and gene expression profiles in cytologically normal bronchial progenitor "basal" cells. The cells were collected from 54 consented bronchoscopy specimen donors at standard airway locations during clinically indicated bronchoscopy, and then outgrown in primary cultures. DNA methylation profiles were assessed using Enzymatic-Methyl sequencing (EM-seq: 96% genomic coverage, 7.5x depth) in all 54 donors' samples. The gene expression profile was evaluated by bulk RNA-Seq in 39 donors' samples. The study participants were at the ages of 33 - 81 years old at enrollment. Of the 54 donors, 31 were newly diagnosed with lung cancer. As for tobacco smoke exposure, there were 19 current, 18, former, and 17 never smokers. There are 26 subjects whose specimens were used for single cell whole-genome sequencing study phs002758.

  Study phs003317

• Mapping_regulatory_variation_in_sensory_neurons_using_IPS_lines_from_the_HIPSCI_project

  Sensory neurons are nerve cells that are activated by sensory input such as heat, light and convey information to the brain. Although a key cell type in complex organisms, human sensory neurons are challenging to study because they are impossible to obtain from living donors. We have collaborated with the Neucentis Pharmaceutical Research Unit to differentiate sensory neuron like cells from human induced pluripotent stem cells derived as part of the Human Induced Pluripotent Stem Cells Initiative. We will sequence RNA from 100 IPS lines derived from healthy individuals and perform RNA-seq on the differentiated cells to identify noncoding variants that alter gene expression in human sensory neurons.

  Study EGAS00001001149

• Family Investigation of Nephropathy and Diabetes (FIND) Study

  The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic kidney disease. Study subjects were recruited from eleven centers and in many ethnic groups throughout the United States. A genome-wide association study (GWAS) was conducted with the Affymetrix 6.0 chip. Subjects (index cases) with diabetes and kidney disease were initially recruited, and their parents and siblings were invited to participate. Genetic material from these participants was used to genotype markers throughout the genome. For association-based testing, a case-control design was implemented with study subjects selected primarily from the index cases of the families. Unrelated controls were selected from families where a case was not already selected. Several study sites also contributed non-FIND subjects, both cases and controls (consent forms for the release of FIND and non-FIND subjects/samples are included in this dbGaP release). Cases were selected if they met study criteria for diabetic nephropathy or met inclusion criteria based on elevated serum creatinine levels and abnormal urine protein excretion. Similarly, controls were long-term diabetics with otherwise normal kidney function. See inclusion/exclusion criteria section for a detailed description for the FIND study as a whole and this GWAS. The goal of the FIND study is to identify genes that influence susceptibility to diabetic kidney disease, leading to a better understanding of how kidney disease develops. In the long run, this may lead to improved treatment and prevention of diabetic kidney disease.

  Study phs000333

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

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

  Study phs000955

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML

  Background Massively parallel sequencing technology has transformed cancer genomics. It is now feasible, in a clinically relevant time-frame, for a clinically manageable cost, to screen DNA from patient tumours for mutations essentially genome-wide. The challenge for personalised medicine will be to increase the sample size to thousands or tens of thousands of well-characterised cases in order to attain sufficient statistical power to stratify patients accurately across the complexity and genomic heterogeneity expected for most of the common tumour types. Currently, whole genome sequencing on this scale is not feasible, and targeted sequencing of relevant portions of the genome will be required. Pilot data We have developed protocols for large-scale, multiplexed sequencing of 100-200 genes in thousands of samples. Essentially, using robotic technology, genomic DNA from the cancer specimen is processed into sequencing libraries with unique DNA barcodes, thereby allowing sequencing reads to be attributed to the sample they derive from. Currently, these sequencing libraries can be generated in a 96-well format using fully automated protocols, and we are exploring methods to expand this to a 384-well format. The sequencing libraries are pooled and hybridized to custom sets of RNA baits representing the genomic regions of interest. Sequencing of the pulled-down libraries is done in pools of 48-96 samples per lane of an Illumina Hi-Seq. This protocol is already implemented at the Sanger Institute. We have published proof that somatic mutations in novel cancer genes can be identified from exome-wide sequencing. In unpublished pilot data, we have established the feasibility of robotic library production, custom pull-down, and multiplexed sequencing of barcoded libraries for 100 known myeloid cancer genes across 760 myelodysplasia samples. Highlights of the data thus far analysed reveal that the coverage is remarkably even between samples; when 96 samples are run, average coverage per lane of sequencing is ~250, with 90-95% of targeted exons covered by >25 reads; known mutations can be discovered in the data set; and the protocol is amenable to whole genome amplified DNA. The bioinformatic algorithms for identification of substitutions and indels in pull-down data are well-established; we have pilot data proving that copy number changes, LOH and genomic rearrangements in specific regions of interest can also be identified by tiling of baits across the relevant loci. Proposal We propose to apply this methodology to 10000 samples from patients with AML enrolled in clinical trials over the last 10-20 years. Oncogenic point mutations and potentially genomic rearrangements will be identified, and linked to clinical outcome data, with a view to undertaking the following sorts of analyses: • Identification of co-occurrence, mutual exclusivity and clusters of driver mutations. • Correlation of prognosis with driver mutations and potentially gene-gene interactions • Exploration of genomic markers of drug response Ultimately, we would like to be in a position to release the mutation data together with matched clinical outcome data to genuine medical researchers via a controlled access approach, possibly within the COSMIC framework (www.sanger.ac.uk/genetics/CGP/cosmic/). The vision here is to generate a portal whereby a clinician faced with an AML patient and his / her mutational profile can obtain a ‘personalised’ prediction of outcome, together with a fair assessment of the uncertainty of the estimate. With a sufficient sample size, there would also be the potential to develop decision support algorithms for therapeutic choices based on such data.

  Study EGAS00001000408

• Whole Exome Sequencing

  Whole Exome Sequencing Data for 10 patients for treatment with the ICI Nivolumab

  Dataset EGAD00001011117

• A thymic ILC1-like progenitor with differentiation potential towards KIR+NKG2A- NK cells

  KIR+NKG2A- Natural Killer (NK) cells have the unique ability to detect downregulation of single HLA-I allotypes, frequently occurring in malignantly-transformed and virus-infected cells in order to escape T cell recognition. We have recently shown that circulating Innate Lymphoid Cells 1 (cILC1) have the potential to generate such KIR+NKG2A- NK cells but their developmental origin was unknown. Here we demonstrate that the development of cILC1 is thymus-dependent and identify a putative progenitor of cILC1s in the thymus, called thyILC1. Single-cell RNAseq analysis revealed a close relationship of thyILC1s to CD34+ double-negative (DN) thymocytes, but in contrast to DNs, thyILC1s had lost T cell differentiation potential. However, like cILC1s they could be efficiently differentiated into KIR+NKG2A- NK cells. thyILC1s strongly expressed RAG1/2, PTCRA (preTCR, and NOTCH1/3, but lacked expression of TCR chains, suggesting that they failed to pass the -selection checkpoint of thymocyte development. Finally, analyses of patients with FOXN1het deficiency, showing thymic hypoplasia due to lack of mature thymic epithelial cells, exhibited a profound deficiency of cILC1s but not cILC2s and cILC3s, demonstrating thymus dependency of cILC1s. Together, the data suggest that thyILC1s are the source of a novel thymus-dependent NK cell differentiation pathway that promotes generation of KIR+NKG2A- NK cells.

  Study EGAS50000000760

• A thymic ILC1-like progenitor with differentiation potential towards KIR+NKG2A- NK cells - sc

  KIR+NKG2A- Natural Killer (NK) cells have the unique ability to detect downregulation of single HLA-I allotypes, frequently occurring in malignantly-transformed and virus-infected cells in order to escape T cell recognition. We have recently shown that circulating Innate Lymphoid Cells 1 (cILC1) have the potential to generate such KIR+NKG2A- NK cells but their developmental origin was unknown. Here we demonstrate that the development of cILC1 is thymus-dependent and identify a putative progenitor of cILC1s in the thymus, called thyILC1. Single-cell RNAseq analysis revealed a close relationship of thyILC1s to CD34+ double-negative (DN) thymocytes, but in contrast to DNs, thyILC1s had lost T cell differentiation potential. However, like cILC1s they could be efficiently differentiated into KIR+NKG2A- NK cells. thyILC1s strongly expressed RAG1/2, PTCRA (preTCR, and NOTCH1/3, but lacked expression of TCR chains, suggesting that they failed to pass the -selection checkpoint of thymocyte development. Finally, analyses of patients with FOXN1het deficiency, showing thymic hypoplasia due to lack of mature thymic epithelial cells, exhibited a profound deficiency of cILC1s but not cILC2s and cILC3s, demonstrating thymus dependency of cILC1s. Together, the data suggest that thyILC1s are the source of a novel thymus-dependent NK cell differentiation pathway that promotes generation of KIR+NKG2A- NK cells.

  Study EGAS50000000790

• NHGRI GREGoR Consortium: Genomics Research to Elucidate the Genetics of Rare Disease

  The NHGRI GREGoR (Genomics Research to Elucidate the Genetics of Rare Disease) Consortium was established in June 2021 with the goal of developing novel tools and approaches to advance the discovery of the genetic basis of rare conditions. Numerous types of molecular data are generated in GREGoR and available on the AnVIL cloud platform via dbGaP application, including short- and long-read genome and exome sequencing, transcriptomics, metabolomics, methylomics, and proteomics. De-identified clinical and demographic data is obtained, with a focus on standardized ontologies.Visit the GREGoR Consortium data webpage for summary information about the GREGoR Dataset, including numbers of participants and data types, methods documentation, and Release Notes. The Consortium comprises five Research Centers (RCs - see below), a Data Coordinating Center (DCC), and various partner members and external collaborators.Baylor College of Medicine Research Center (BCM-GREGoR) The Baylor College of Medicine GREGoR program, which is part of the GREGoR consortium, enrolls individuals, families, and cohorts with suspected rare disease across a range of syndromic and non-syndromic phenotypes. Subjects are enrolled from national and international collaborating physician referrals. Subjects provide written informed consent for future re-contact. Data generated and shared include family structure, detailed phenotypes, exome or short-read genome data, and in some cases long-read genome or RNA-sequencing, and these are shared upon completion of standard quality control checks and annotation. Broad Institute (Broad) The Broad Center for Mendelian Genomics, part of the GREGoR consortium uses next-generation sequencing (exome, genome, transcriptome, and long read sequencing), computational approaches, and functional studies to discover the variants and genes that underlie Mendelian conditions with a particularly focus on neuromuscular, neurodevelopmental, and syndromic phenotypes. Samples come from collaborators and direct enrollment through the Rare Genomes Project and we are committed to rapid data sharing without an embargo period. University of California, Irvine (UCI-GREGoR) To accelerate the pace of Mendelian disease gene discovery and clinical implementation, we propose a Mendelian Genomics Research Center, part of the GREGoR Consortium, leveraging the broad pediatric and adult clinical and research expertise at Children's National Hospital and University of California, Irvine. Our goal is to develop best practices to increase the diagnostic yield of rare diseases, engage the community to reduce health disparities for complex diagnoses, while creating a dataset accessible to all. Our Center will unite world class experts combining basic and translational research with innovative approaches to phenotyping, variant identification and functional investigation of both coding and non-coding sequence changes with the goals of discovering novel Mendelian gene variations and identifying variants not detected on current sequencing pipelines, disambiguating uncertain variants into disease-causing versus benign categorizations, and sharing information by working collaboratively with the GREGoR community.GREGoR Stanford Site (GSS) The goal of the GREGoR Stanford Site (GSS) is to provide a platform for functional genomics research and validation to improve diagnosis in Mendelian disease. Participants included individuals with undiagnosed suspected Mendelian disease who had non-diagnostic exome sequencing and their immediate family members. Participants and their family members provided written, informed consent and biological samples from which DNA, RNA, plasma, fibroblasts, PBMCs and other cell types were generated and stored. Samples from research participants and their immediate family members may have undergone short and long-read genome sequencing, transcriptome sequencing, metabolomics and/or lipidomics profiling, methyl-capture-sequencing and ATAC-sequencing. De-identified clinical data extracted from participant medical records are linked to the samples. University of Washington Center for Rare Disease Research (UW-CRDR) The goals of the University of Washington Center for Rare Disease Research are to: (1) maximize novel gene discovery for Mendelian conditions by recruitment, short- and long-read whole genome sequencing, transcriptome sequencing and analysis of families with rare conditions for which the gene is either unknown or the gene is known but no pathogenic variant can be identified via clinical testing; (2) develop new strategies for gene discovery for Mendelian conditions caused by variants that are difficult to detect using conventional testing strategies, variants of unknown function effect (e.g., regulatory, structural variants) or have unusual modes of inheritance; and (3) implement high-throughput screening and targeted follow-up functional studies to prioritize and validate candidate non-coding variants. De-identified data and phenotypic information are shared via MyGene2, ClinVar, and AnVIL.

  Study phs003047

• HELIUS DAC The HELIUS data are owned by the Amsterdam University Medical Centers, location AMC in Amsterdam, The Netherlands. To allow sharing of microbiome data collected in HELIUS with (inter)national researchers, 16s rRNA sequence analysis has been stored at the European genome-phenome archive (EGA; accession code EGAD00001004106). This requires that access needs to be granted, also because the HELIUS data are stored with relevant phenotypical variables. Access is granted to all researchers affiliated with an internationally recognized research institution who request to use the HELIUS data within the EGA context, after having signed the data transfer agreement. Any researcher can request the data by submitting a proposal to the HELIUS Executive Board as outlined at http://www.heliusstudy.nl/en/researchers/collaboration, by email: heliuscoordinator at amsterdamumc dot nl. The HELIUS Executive Board will check proposals if they do not conflict with ethical approvals and informed consent forms of the HELIUS study.

  Dac EGAC00001000895

• RNA-seq as a tool for evaluating human embryo competence

  The majority of embryos that are created through IVF do not implant. One possibility for this inefficiency is an incomplete understanding of the molecular factors affecting embryo competence. Currently, the process of selecting an embryo for uterine transfer utilizes an ad-hoc combination of morphological criteria, the kinetics of development, and genetic testing for aneuploidy. However, no single criterion can ensure selection of a viable embryo. In contrast, RNA-sequencing of embryos could yield highly dimensional data, which may provide additional insight and illuminate the discrepancies among current selection criteria. Indeed, recent advances enabling the production of RNA-sequencing (RNA-seq) libraries from single cells have facilitated the application of this technique to the study of some transcriptional events in early human development. However, these studies have not assessed the quality of their constituent embryos relative to commonly used embryological criteria. Here, we perform proof-of-principle advancement to clinical selection procedures by generating high quality RNA-seq libraries from a trophectoderm biopsy as well as the remaining whole embryo. We combine state-of-the-art embryological methods with low-input RNA-seq to develop the first transcriptome-wide approach for use in future predictive embryology studies. Specifically, we demonstrate the capacity of RNA-seq as a promising tool in preimplantation screening by showing that biopsies of an embryo can capture valuable information content available in the whole embryo from which they are derived. Furthermore, we show that this technique can be used to generate a RNA-based digital karyotype, and to develop a foundational dataset for identifying candidate competence-associated genes. Together, these data establish the foundation for a future RNA-based diagnostic in IVF.

  Study EGAS00001003667

• Long-read and short-read isoform sequencing in breast cancer

  The goal of this project was to perform long-read RNA sequencing (LR-seq, PacBio) in combination with short-read RNA-seq for systematic characterization of the isoform diversity in primary breast tumor samples. We sequenced the full-length transcriptomes of 26 breast tumors and 4 normal breast samples.

  Study EGAS00001004819

• Discovery of Colorectal Cancer Susceptibility Genes in High-Risk Families

  Colorectal cancer remains one of the most common cancers in the US with 146,970 new diagnoses and 49,920 deaths estimated for 2009. Colon cancer is also one of the most familial of cancers. Individuals with a first-degree relative with colon cancer have a 2- to 3-fold increased risk, and those with more than one first-degree relative with colon cancer, or a single first-degree relative affected at age 50 years, have a 3- to 6-fold greater risk than those with no family history. The most prominent high-risk colorectal cancer susceptibility genes, APC, MLH1, MSH2, MSH6, and PTEN, were all discovered more than a decade ago. Currently, mutation screening of these genes, plus a short list of additional genes that are responsible for a very small fraction of colorectal cancer, plays an important role in the clinical management of individuals with a strong family history of the disease or syndromic evidence for the presence of a gene mutation. At the other end of the risk spectrum, genome-wide association studies have identified a number of common alleles with very modest effects on colorectal cancer risk; their clinical utility has yet to be established. However, taken together, the known spectrum of genetic effects only explain about one quarter of the overall familial excess of colorectal cancer. It should be emphasized that, at present, the vast majority of individuals seen at familial cancer clinics are counseled on the basis of their family history alone because they do not have mutations in the known susceptibility genes. Accordingly, the long-term objective of this project is to identify the majority of genes responsible for the unexplained component of inherited colorectal cancer risk. Nextgen DNA sequencing is well suited for application to research questions in genetic susceptibility for which linkage analysis is confounded by extensive genetic heterogeneity. Taking advantage of unparalleled familial cancer genetics resources available through the Utah Population Database, candidate genes have been identified by sequencing all of the gene exons in the human genome from a series of colorectal cancer cases with a very strong family history of colorectal cancer not explained by one of the currently known high-risk susceptibility genes.

  Study phs001787

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

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

  Study EGAS50000001383

• SDH_deficient_renal_tumours___WGS_

  Succinate dehydrogenase (SDH) deficient renal cancers are a rare and understudied subtype of renal cancer. As such they represent an unmet need in kidney cancer research. Here, we seek to describe the genomics and transcriptomics of SDH deficient renal cancers by sequencing five such tumours. We document their mutational burden, define driver mutations, demonstrate typical patterns of structural variants, and estimate the cell of origin and cellular composition.

  Study EGAS00001004102

• The EGA Helpdesk team: 2025 in review and what we are building next

  Behind every dataset submitted, every access request processed, and every technical question answered, there is a team working quietly to keep things moving: the Helpdesk (HD). With the onset of 2026, this feels like the right moment to look back on what 2025 has been like for the HD team: the challenges we faced, how we adapted, and where we're heading next. Why the Helpdesk matters to EGA The EGA Helpdesk is more than a support channel. It plays a key role in maintaining trust in the EGA ecosystem. By supporting data submitters, researchers, Data Access Committees (DACs), and institutional partners, the HD helps ensure that data can flow securely, efficiently, and reliably. When issues arise, the Helpdesk is often the first place where their impact is felt and addressed. In that sense, the HD sits at the intersection of technology, policy, and people. One Helpdesk, two locations, one shared mission The EGA Helpdesk is a joint, distributed team working closely across two locations: CRG (Barcelona, Spain) and EMBL-EBI (Cambridge, UK). Although we are based in different institutions, we operate as a single Helpdesk, with shared workflows, priorities, and responsibility towards users. At CRG, the HD team is formed by: Andrea Max Àlex and me At EMBL-EBI, we work closely with: Silvia Coline Aravind What defines us as a team is simple: we work user-first, even under pressure. In a highly technical environment, clarity, empathy, and consistency matter just as much as tools and processes. A close collaboration across sites is essential to making that happen. What does the EGA Helpdesk do? The HD supports users across the full lifecycle of data in EGA. This includes: Data submissions, uploads, and encryption workflows. Data access requests and permissions. Questions around policies, consent, and data usage. Technical and system-related issues. Coordination between users, internal teams, and external partners. 2025: growth, change, and recalibration 2025 was a year of growth, but not always a predictable one. Early in the year, several technical and system-related challenges required us to adjust our original plans. Priorities shifted, timelines changed, and some improvements had to be rethought. For the HD team, this is often the hardest part of the job: we see delays through the eyes of users and understand the real impact they can have on ongoing research. One of the key lessons from 2025 was that stability is not only a technical challenge, but also an organisational one. Teamwork proved to be essential: anticipating peak periods, sharing context early, and coordinating closely across teams made a tangible difference. When things became complex, working together across roles and locations was what allowed us to keep moving forward. In 2025, the Helpdesk received 5.313 tickets and resolved 5.511 requests, reflecting both increased adoption of EGA and the team’s ability to absorb higher demand. At the same time, demand continued to grow. Compared to 2024, ticket creation increased by over 6%, while resolution capacity grew by more than 11%. The team not only kept up with incoming requests but also resolved part of the accumulated backlog, finishing the year having solved more tickets than were created. The real challenge of 2025 was not overall performance, but how the workload was concentrated during peak months. Seasonality and demand spikes placed pressure on the system, even while overall efficiency remained strong. On a team level, 2025 was also a year of transition. I joined the HD leadership role in January 2025, stepping into a period of change and rapid learning. Later in the year, in October, we said goodbye to Raül, and in January 2026, we welcomed Àlex, strengthening the team for the next phase. What users needed most in 2025 While requests vary widely, some themes stood out throughout the year: Support with data submissions and uploads Data access requests and permissions Technical and system-related issues As EGA matures, day-to-day operations have become more complex. Many long-running tickets are not delayed due to a lack of follow-up, but because they depend on external approvals, cross-institutional coordination, or multi-step processes. Understanding these patterns helps us focus not just on resolving tickets, but on improving how work flows through the system. Looking ahead to 2026 With a reinforced team and clearer insights from 2025, our focus for 2026 shifts from throughput to flow. Key priorities include: Strengthening our web content and documentation Reducing structural backlog Improving cross-team and cross-system coordination Anticipating peak demand earlier and planning capacity accordingly Challenges will continue to arise in 2026, as they always do. However, 2025 reinforced something important: a stable, empathetic, and well-aligned Helpdesk team is essential to supporting EGA's mission at scale. Supporting users well means supporting research, and that remains at the core of what we do.

  Blog ega-helpdesk-team-2025-in-review-and-upcoming-improvements

• Privacy Notice for Helpdesk service

  Privacy Notice for EGA Helpdesk service This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org , or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from users of the service: Name Email address Job title Date and time when the support request was sent We will use your personal data for the following purposes: To provide uninterrupted user access to the service To better understand the needs of the users and guide future improvements of the service To create anonymous usage statistics 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? There are no personal data transfers to third countries or international organizations. 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-helpdesk

• Target sequencing of 27 cancer-predisposing genes and 13 renal cell carcinoma-related genes in Japanese renal cell carcinoma patients

  Identifying causative genes via genetic testing is useful for the screening, prevention, and treatment of cancer. Several hereditary syndromes are known to occur in renal cell carcinoma (RCC). However, these evidences came from the European population; it remains unclear how the RCC-related genes and other cancer-predisposing genes contribute to the development RCC in the Japanese population. A case-control study of 14 RCC-related genes and 26 cancer-predisposing genes was performed using 1,563 Japanese patients with RCC and 6,016 controls. Patients were divided into two major histological subtypes of clear cell RCC (ccRCC) or non-clear cell RCC (nccRCC). Gene-based analysis of germline pathogenic variants in patients with each subtype and cancer-free subjects was performed. Following quality control, 1,532 patients with RCC and 5,996 controls were further analyzed. For ccRCC, 52 of 1,283 (4.05%) patients carried pathogenic variants mainly in the cancer-predisposing genes such as TP53 (P = 1.73 �� 10-4; OR, 5.8; 95% CI, 2.2���15.7). Approximately 80% of patients with pathogenic variants in TP53 had p.Ala189Val that was specific in East Asian population. For nccRCC, 14 of 249 (5.62%) patients carried pathogenic variants mainly in the RCC-related genes such as BAP1 (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf), and FH (P = 6.27 �� 10-5; OR, Inf; 95% CI, 10.0���Inf). Our study showed different and population-specific contributions of risk genes between ccRCC and nccRCC in Japanese for better-personalized medicine.

  Study JGAS000414

• Whole-exome/genome sequencing of childhood acute leukemia in Iraq

  This dataset contains 26 whole-genome sequencing (13 paired tumor and normal), 106 whole-exome sequencing (53 paired tumor and normal), and 43 targeted sequencing data. Sequencing was performed using an Illumina platform. The data are BAM files aligned to the hg19 reference genome.

  Dataset EGAD00001007873

• Small‑scale mutations are infrequent as mechanisms of resistance in post‑PARP inhibitor tumour samples in high grade serous ovarian cancer

  Targeted DNA sequencing of high-grade serous ovarian cancer (HGSC) tumour and normal samples from 26 patients. Following target hybrid capture of 63 genes involved in DNA repair and response to treatment with an Agilent SureSelect XT panel, sequencing libraries were generated using the SureSelect XT Low Input Target Enrichment System (Agilent) as per the manufacturer's protocol. Libraries were sequenced on an Illumina NextSeq 500 at the Peter MacCallum Cancer Centre (Melbourne, Australia).

  Study EGAS50000000146

• Confirmation of a founder effect in a Northern European population (FRL) of a new beta-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA))

  Beta-thalassemia is a genetic disease caused by a defect in the production of the beta-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of 4 nucleotides in the first exon of beta-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the beta-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (9 generations). In order to determine whether this variant arose in this region of Northern-Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare beta-thalassemia variants have already been described in patients sampled in non-endemic regions but it is the first proof of a founder effect in Northern Europe. The new genetic panel FRL is under registration in EGA.

  Study EGAS00001000980

• Profiling of 27 type 2 diabetes GWAS loci using next-generation (NG) capture C in a human beta-cell model

  Most type 2 diabetes association signals are due to variants that impact gene regulation but identifying the genes they impact is challenging. We generated interaction profiles at 27 T2D GWAS loci using next-generation (NG) capture C (6 replicates) in the human beta-cell model, EndoC-betaH1, along with chromatin accessibility profiling using ATAC-Seq (9 replicates).

  Dataset EGAD00001008655

• A Genome-Wide Association Analysis in Angiotensin-Converting Enzyme (ACE) Inhibitor-Associated Angioedema and ACE Inhibitor-Exposed Controls; A Collaboration between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Center for Genomic Medicine

  The purpose of this study is to identify genetic predictors of ACE inhibitor-associated angioedema. In addition to preventing the formation of the pressor angiotensin II, ACE inhibitors prevent the carboxyl-terminal degradation of the vasoactive substances bradykinin and substance P. Angioedema is hypothesized to result from defective amino-terminal degradation of bradykinin or substance P in patients in whom ACE is inhibited. For example, activity of dipeptidyl peptidase IV (DPP-IV), the enzyme responsible for the inactivation of substance P when ACE is inhibited, is decreased in patients with angioedema. In preliminary studies, we have identified SNPs in the DPP4 gene that associate with DPP-IV activity and, in blacks, with risk of angioedema. This project will use genome-wide genotyping to compare 250 cases and 568 ACE inhibitor-exposed control subjects (131 cases and 288 controls ascertained at Vanderbilt and 70 cases and 280 controls ascertained at the Marshfield Clinic). We plan a 2-stage analysis of associations between SNPs and angioedema - first, we will study DPP4 SNPs for association with angioedema and, second, we will explore associations using the full GWAS data set. Depending on the platform, additional DPP4 SNPs will be used to fully tag common genetic variants in both African American and European American samples. Based on the HapMap data, there are 14 tagging SNPs in people of European descent and 34 in Yoruba (selection criteria MAF>0.05 and r2>0.8). Cases were defined as having ACE inhibitor-associated angioedema if they had had swelling of the lips, throat, tongue or face while taking an ACE inhibitor but had never had angioedema while not taking an ACE inhibitor. For simplicity, intestinal edema was excluded. Control subjects were treated for at least 6 months with an ACE inhibitor without angioedema. Because black Americans are known to be overrepresented among patients with ACE inhibitor-associated angioedema, control subjects were prespecified to be 50% black American, 50% white American, and 50% female. At Vanderbilt, the medical history, including the history of angioedema, was confirmed by a research nurse or physician using a detailed case report form. Characteristics of Vanderbilt cases appear in the Table. At Marshfield, medical history will be confirmed by chart review. The Marshfield cohort is 98% white American and 57% female with a mean age of 47.2 years.

  Study phs000438

• Rare germline sequence variants, copy number variations, expression alterations, methylation variations and disease susceptibility in familial melanoma

  Although a number of high-risk melanoma genes have been identified, they account for melanoma risk in less than 40% of melanoma-prone families. The major goals of our research are to identify novel high-penetrance genes for familial melanoma in melanoma-prone families without known mutations and to identify modifier factors, including genetic and epigenetic, in melanoma-prone families with and without known major mutations. We are using whole exome sequencing to identify additional high-risk susceptibility genes and using targeted sequencing to follow up on the top genes in additional family members and in population-based melanoma cases and controls. We are also using RNASeq to investigate genome-wide allele-specific expression and eQTLs in these families to identify genes with expression alteration, which will provide additional information for gene discovery. In addition, we also conducted genome-wide copy number variation (CNV), methylation, and miRNA expression profiling analyses in our melanoma families with the goal of identifying genetic and epigenetic factors as disease modifiers.

  Study phs001177

• Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pointine Glioma

  Diffuse Intrinsic Pontine Gliomas (DIPG) are deadly pediatric brain tumors where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, we analyzed 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3)K27M – including novel H3.2K27M - mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumor and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumor spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

  Study EGAS00001001654

• PFA ependymoma study -WGS data

  WGS bam file for the 18 samples used in Michealraj et al. Cell 2020. The dataset includes PFA ependymoma tissue, derived line and blood samples of 6 patients WGS data were aligned with BWA to the hg38 human reference genome (igenome) and further processed according to the GATK best practice pipeline.

  Dataset EGAD00001006045

• PCGP Ph-like ALL

  Background: BCR-ABL1-like, or Ph-like acute lymphoblastic leukemia is characterized by a gene expression profile similar to BCR-ABL1 positive ALL, genetic alterations of lymphoid transcription factor genes, and poor outcome. Sequencing of small numbers of Ph-like ALL cases has identified genetic alterations activating kinase signaling suggesting Ph-like ALL may be amenable to treatment with tyrosine kinase inhibitors. However, the spectrum of genetic alterations in childhood and adult Ph-like ALL is incompletely understood. Methods: We performed genomic profiling of 1736 B-ALL cases and next-generation sequencing for 160 Ph-like cases. We examined the functional effects of chimeric fusion proteins in mouse cell lines. Results: The frequency of Ph-like ALL rose from 11% in children to 26% in young adults, and was associated with very poor outcome. Kinase-activating alterations were identified in 90% of Ph-like cases, most commonly fusions involving 10 kinase or cytokine receptor genes (ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B and TYK2), and mutations involving FLT3, IL7R and SH2B3. Expression of ABL1, ABL2, CSF1R and JAK2 fusions resulted in cytokine-independent proliferation of cell lines and activation of pSTAT5. Cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions were sensitive to dasatinib, and JAK2 fusions to ruxolitinib. Conclusions: Ph-like ALL is characterized by a diverse range of genomic alterations that converge on a limited number of kinase signaling pathways amenable to inhibition with currently available tyrosine kinase inhibitors. Trials identifying Ph-like ALL and testing the efficacy of tyrosine kinase inhibitor therapy are warranted

  Study EGAS00001000654

• Development and Validation of a Disability Severity Index for Charcot-Marie-Tooth Disease (CMT)

  In Charcot-Marie-Tooth Disease (CMT) or inherited neuropathy research studies, it is the researcher who has selected what they believe to be important markers of impairment in function in patients. For example, it has been inferred that the wearing of ankle-foot-orthosis (AFOs), the use of walking aids such as canes, or the use of wheelchairs, are appropriate markers for “mild”, “moderate” or “severe” disability, respectively. Whether patients agree with this classification is unknown. By understanding what patients classify as mild, moderate and severe disability in CMT, we will know what our treatments need to target, to have a meaningful impact on the patients' functional status. Primary objective: The purpose of this study is to compare patient and healthcare provider impressions of what constitutes mild, moderate and severe disability in CMT. Target population: 200 patients who have self-registered at the Inherited Neuropathy Consortium Contact Registry, a web-based contact registry developed and supported by the Data Management and Coordinating Center (DMCC) for the Rare Diseases Clinical Research Consortium (RDCRN), located at the University of South Florida, and 200 health care professionals attending conferences about CMT, such as the 4th International CMT Consortium to be held in Potomac, Maryland, June 29-July 1, 2011 and the MDA Clinic Directors meeting in Las Vegas, NV March 4-7, 2012. Methods: A brief, anonymous, 20-item survey, in which we measure what the physician and the patient think are important indicators of disability in CMT, will be distributed by paper to 200 health care professionals, and via an online link to 200 patients self-registered with the RDCRN contact registry. Out of the 200 patients, approximately 25 patients will be requested to take the survey twice in a 2 to 4 week period. Analysis: We will measure the agreement between items in the physician and patient groups, and use items with high agreement in a Disability Severity Index.

  Study phs001295