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• Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics

  Epithelioid sarcoma (EpS) is an aggressive sarcoma, characterized by the loss of SMARCB1 expression. EpS is traditionally classified as distal or proximal according to clinicopathological features, but its molecular characteristics remain largely unknown. To establish an EpS molecular classification and uncover determinants of inter- and intra-patient heterogeneity in EpS, we used multi-omics profiling and integrated the genomic, transcriptional and methylome landscapes with single-cell RNA sequencing on fresh samples as well as spatial transcriptomics. We identified two molecular subtypes of EpS: “distal-like” and “proximal-like”, which were distinct from the histological subtypes. Distal-like tumors include all morphological distal subtypes and a subset of proximal and hybrid EpS. They express a specific molecular single-cell derived epithelial-to-mesenchymal transition signature, which associates with improved patient survival and includes Desmoglein 2 (DSG2), which we identify as a potential routine immunohistochemical biomarker to improve diagnosis. Distal-like EpS also display increased peri-tumoral CD8+ T cell infiltrates and specific tumor-immune cell interactions. Conversely, proximal-like EpS harbor a higher inter-tumoral molecular heterogeneity with some cases resembling other SMARCB1-deficient tumors by DNA methylation profiling, and increased intra-tumoral pro-tumoral macrophage infiltrates. Our study introduces a novel molecular classification of EpS with prognostic value, associated diagnostic biomarkers and distinct tumor immune microenvironments, which extends beyond traditional clinicopathological classification. This paves the way for precision medicine-based therapeutic strategies for patients with EpS.

  Dac EGAC50000000552

• DNA methylation atlas of normal human cell types

  DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

  Study EGAS00001006791

• NHLBI TOPMed - NHGRI CCDG: Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. For the TOPMed WGS project only early-onset atrial fibrillation cases were sequenced. Early-onset atrial fibrillation was defined as an age of onset prior to 66 years of age. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs001001.

  Study phs001062

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

  Study phs001238

• Genome-Wide Assessment of DNA Methylation in Systemic Lupus Erythematosus-Related Autoantibodies

  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can have debilitating effects on multiple organ systems. In SLE, the pivotal immunologic disturbance is the formation of autoantibodies directed against nuclear and cellular antigens. These autoantibodies are associated with specific organ manifestations. Our previous work has shown that certain single nucleotide polymorphisms (SNPs) are associated with the production of SLE-related autoantibodies. However, these genetic associations do not completely explain autoantibody development in SLE. Therefore, we examined whether epigenetic factors such as DNA methylation may be associated with the development of SLE-related autoantibodies. In this study, we examined whether differential DNA methylation is associated with anti-dsDNA, anti-SSA/Ro, anti-Smith, and anti-RNP autoantibodies. Using the Illumina HumanMethylation450 Beadchip, over 450,000 DNA methylation sites were characterized in 325 female SLE cases of European descent. Using a multivariable regression analyses, the methylation status of 16 CpG sites in 11 genes was found to be associated with the SLE-related autoantibodies under study. This study shows that epigenetic factors are associated with autoimmune disease phenotypes, and epigenetic studies are a complementary method to genetic association studies for understanding the biologic mechanisms contributing to autoimmune disease.

  Study phs000947

• Federated discovery and sharing of genomic data using Beacons

  The Beacon Project is a Global Alliance for Genomics & Health (GA4GH) initiative that enables genomic and clinical data sharing across federated networks. The project is working toward developing regulatory, ethics and security guidance to ensure proportionate safeguards for distribution of data according to the GA4GH-developed “Framework for Responsible Sharing of Genomic and Health-Related Data”. Within this Nature Biotechnology Correspondence a description of the Beacon protocol and how it can be used as a model for the federated discovery and sharing of genomic data is offered to the community. A Beacon is defined as a web-accessible service that can be queried for information about a specific allele. A user of a Beacon can pose queries of the form “Have you observed this nucleotide (e.g., C) at this genomic location (e.g., position 32,936,732 on chromosome 13)?” to which the Beacon responds with either “yes” or “no.” In this way, a Beacon allows allelic information of interest to be discovered by a remote searcher with no reference to a specific sample or patient, thereby mitigating privacy risks. The Beacon API (represented as a RESTful web application) provides a technical specification that a Beacon server must implement. The specification is open source and available online here. To simplify the process of lighting a Beacon, a free, open-source reference implementation of the latest specification has been developed. GA4GH is promoting different levels of data access (open, registered, and controlled) for convenience and for compatibility across its projects. Each so-called access tier has distinct visibility and requirements for authorization. For example, ‘open access’ Beacons are accessible to anonymous users of the internet, whereas ‘registered access’ Beacons are accessible to registered users (for example, bona fide researchers and clinicians) who have agreed to a set of conditions of data use. Many of the largest genomic archives, such as dbGaP, the European Genome-phenome Archive and the European Variation Archive, have provided access to variation data through Beacons for some or all of their datasets. Beacons can be interconnected through the Beacon Network, a directory and search engine for Beacons. Although individual Beacons answer the question “Have you observed this allele?”, the Beacon Network answers the question “Who has observed this allele?”. Beacons can be freely registered to the Beacon Network and can be searched independently or in aggregate with other connected Beacons.

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• TCGA WGS Variants Across 18 Cancer Types

  Even though whole genome sequence (WGS) data has been generated and published in many studies, much of this information is not yet processed for use in down-stream analysis. This study's aim is to provide 1342 WGS normal-tumor paired single nucleotide variations (SNP) over 18 different cancer types provided by The Cancer Genome Atlas (TCGA) project. Individual level data for TCGA can be accessed by requesting access for phs000178. This data includes variations within self-reported white and African-American populations. Variations that exist within the tumor tissue but are absent in associated normal organ tissue (as compared to the human reference genome) are reported. Data published includes SNP and small insertions and deletions, which were generated through a pipeline including the VarScan2 variant calling software.

  Study phs003155

• Illumina HumanCoreExome genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanCoreExome BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotypes were called using GenCall (Illumina Genome Studio) followed by zCall and quality control (QC) was performed in two stages (pre- and post-zCall).

  Study EGAS00001001001

• Genetics of Antinuclear Antibodies

  Antinuclear antibodies (ANA) are antibodies that react against self-antigens in the cell. While it has been reported that 12 to 20% of the general population have a positive ANA test, the genetics of ANA positivity is unknown. We performed a genome wide-association study for positive ANA tests among individuals without an ANA related autoimmune disease in the Vanderbilt University Medical Center (VUMC) DNA biobank linked to the de-identified electronic health record (EHR) system. The study is funded by the National Institute of Arthritis and Musculoskeletal and Skin diseases (NIAMS) grant R01AR076516.

  Study phs003189

• The Oral Mycobiome and Risk of Pancreatic Cancer

  The purpose of our study was to assess the influence of oral microbiota on the development of pancreatic cancer. Our preliminary case-control studies showed that oral carriage of a periodontal pathogen is related to increased risk for pancreatic cancer. We hypothesize that the oral bacteria and fungi are associated with risk of pancreatic cancer. We conducted a prospective study nested in two large well-established U.S. cohorts to determine whether the oral bacterial and fungal microbiome is associated with subsequent risk of pancreatic cancer.

  Study phs003994