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• National Institute of Arthritis and Musculoskeletal and Skin Diseases and Istanbul Faculty of Medicine Genome-wide Association Study of Behçet's Disease (Turkish)

  IntroductionBehçet's disease (BD) is a genetically complex multisystem disease of unknown etiology, characterized by recurrent inflammatory attacks affecting orogenital mucosa, eyes, skin, joints, blood vessels, and less frequently, the central nervous system and gastrointestinal tract. Family studies suggest a genetically complex contribution to BD. With the exception of HLA-B51, which explains less than 20% of the genetic risk, the identities of alleles that are responsible for the complex inheritance of this disease have remained unclear. AimTo identify genes that contribute to BD susceptibility. MethodsA genome-wide association study was undertaken with 311,459 informative and high quality SNPs in a collection of 1215 BD patients and 1278 healthy controls from Turkey using a beadchip microarray assay (Infinium SNP genotype assay, Illumina). HLA-B types were determined with a reverse sequence-specific oligonucleotide method (One Lambda). Regions with evidence for association were fine-mapped using Sequenom iPLEX gold assays. Disease-associated SNPs were genotyped in additional ethnically matched case/control collections from diverse genetic backgrounds, including a total of 2430 cases and 2660 controls, using TaqMan SNP genotype assays. Association data were combined in a meta-analysis of all the collections. ResultsWe confirmed the known association with HLA-B51 and found evidence for a second, independent susceptibility locus in the Class I region of the MHC. In addition, we identified one SNP with genome-wide evidence for disease association (P < 5.0 x 10-8) within the gene encoding the immunoregulatory cytokine, interleukin-10 (IL10). A meta-analysis of the data from all the collections established associations with the IL10 variant (rs1518111, P = 3.54 x 10-18, odds ratio 1.45 with 95% confidence interval 1.34 to 1.58) and with a variant located between the interleukin-23 receptor (IL23R) and interleukin 12 receptor β2 (IL12RB2) genes (rs924080, P = 6.69 x 10-9, odds ratio 1.28 with 95% confidence interval 1.18 to 1.39). The disease-associated IL10 variant was associated with diminished mRNA expression and low protein production by cells obtained from healthy blood donors. ConclusionsThese data suggest that genetically encoded low production of IL-10 increases risk of BD and suggest novel interventional targets in the IL-10 and IL-23 pathways. Note: The submitted data are the genotypes of the 311,459 SNPs in 1215 cases and 1278 controls.

  Study phs000272

• Genetic Causes of Congenital Anosmia

  The Genetic Causes of Congenital Anosmia study was designed to provide a list of candidate genes that are potentially causal for isolated congenital anosmia (ICA), a rare inherited disorder where individuals lack a sense of smell from birth in the absence of a known genetic syndrome (i.e. Kallman's syndrome). This study includes 193 participants from 18-87 years of age, divided into two cohorts: family and non-family. Genetic data from the family cohort was analyzed in a case-control family design to generate a list of 162 candidate genes for ICA. A targeted search for variants in this list of genes was then conducted in the non-family cohort to create a prioritized list of genes for further study. Ten unrelated families were recruited for the family cohort for a total of 52 participants, 25 of which had anosmia. The non-family cohort consisted of 141 anosmic individuals. 3 additional normosmic participants from incomplete families were collected, one of whom has a participating family member in the non-family cohort, and so has data provided here. Data collection was conducted remotely, resulting in 146 participants recruited from the United States, and 48 recruited internationally from ten different countries. Participants were interviewed for their anosmia status and to confirm that they had no known genetic syndromes. Participants also completed the University of Pennsylvania Brief Smell Identification Test (BSIT; Doty et al., 1984) to confirm their anosmic/normosmic status and provided a saliva sample for whole exome sequencing (WES). Participants who had family members with anosmia provided pedigree information via interview. Data submitted to dbGap include whole exome sequences from 194 individuals (163 anosmic) conducted with Illumina HiSeq2500 and Illumina NovaSeq next generation sequencing technologies. Family pedigree information for the 10 participating families and all participants in the non-family cohort who have non-participating anosmic family members was also included. Our goal was to provide a resource for further research into the genetics of isolated congenital anosmia and to aide in the understanding of this disorder, as well as human olfaction, in general. The WES data provided could be further analyzed for polygenic interactions, additional non-targeted analysis on the non-family cohort, or combined into databases of other anosmic populations for further gene targeting or selection.

  Study phs003328

• Acute Respiratory Distress Network (ARDSNet) Studies 06 and 08 Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo for the Treatment of Acute Lung Injury (ALTA) (ARDSNet-ALTA-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-ALTA include Plasma, DNA, Urine, and BAL. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives This clinical trial was designed to test the hypothesis that an aerosolized beta-2-agonist, albuterol, would improve clinical outcomes in participants with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Background In participants with acute lung injury and acute respiratory distress syndrome (ALI/ARDS), inflammation of the pulmonary circulation increases vascular permeability. Fluid leaks from blood vessels into the pulmonary interstitium and alveoli. Recovery from this form of acute respiratory failure requires that the pulmonary edema resolve. The resolution of alveolar edema is driven by active transport of sodium and chloride ions from the luminal space across both type I and type II alveolar epithelial cells, creating an osmotic gradient for the reabsorption of water. In the ex vivo human lung, the rate of alveolar fluid clearance can be doubled by treatment with a cyclic AMP beta-2 adrenergic receptor agonist. On the basis of the preclinical observations that treatment with beta-2-agonists could reduce pulmonary edema and accelerate the rate of alveolar fluid clearance, the ALTA study was designed and undertaken with the hypothesis that treatment of participants with ALI/ARDS with beta-agonist therapy would accelerate the resolution of alveolar edema and improve clinical outcomes. Participants There were 282 participants. Design Study staff conducted a multicenter, randomized, placebo-controlled clinical trial in which participants were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Conclusions Ventilator-free days were not significantly different between the albuterol and placebo groups. The results suggest that aerosolized albuterol does not improve clinical outcomes in participants with ALI. Routine use of beta-2 agonist therapy in mechanically ventilated participants with ALI cannot be recommended (Matthay, et al., 2011, PMID: 21562125).

  Study phs003743

• Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP IPF-BioLINCC)

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

  Study phs004314

• The BC Cancer Agency's Personalized Onco-Genomics Project

  The BC Cancer Agency's Personalized Onco-Genomics (POG) Project involves molecular and clinical characterization of individual cancer patients to guide their treatment. The project aims to use whole genome and transcriptome data together with patient information to match treatments to cancer driver alterations and support clinical decision-making. Incorporating genomic data into decision-making should enable more rational development of treatment plans, facilitate enrollment into appropriate clinical trials and potentially identify less toxic and more effective therapeutic options.

  Study EGAS00001001159

• Djerroudi et al., E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

  Invasive lobular breast carcinoma (ILC) shows specific stromal features, T lymphocyte infiltration (TIL) being associated with poor prognosis. Here, we reveal the involved mechanism by performing single cell RNA sequencing, combined immunohistochemistry, deconvolution of bulk RNA sequencing from large retrospective ILC series, and functional assays using primary cells. We show that ILC accumulate FAP+ inflammatory cancer-associated fibroblasts (iCAF) through a previously undescribed mechanism mediated by E-cadherin/CDH1 on CAF plasticity. Indeed, CDH1 inactivation in ILC cancer cells prevents differentiation of iCAF into myofibroblastic CAF (myCAF), leading to iCAF accumulation. In turn, iCAF increase TIL infiltration and shape their spatial organization in ILC. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape by lack of retention and activation of ITGAE-expressing resident memory CD8+ T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, iCAF and CD8+ TRM, revealing why and how TILs have a poor prognosis in ILC patients, a mechanism extrapolated to other CDH1-mutated cancer types.

  Study EGAS50000000761

• METABRIC: Data from Pereira et al (2016), The somatic mutation profiles of 2433 breast cancers refine their genomic and transcriptomic landscapes. Nat Comms 7.

  The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2433 primary breast tumours that have copy number aberration (CNA), gene expression, and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters, and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intratumour heterogeneity using mutant allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intratumour heterogeneity are in general associated with worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intratumour heterogeneity. These results emphasise the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

  Study EGAS00001001753

• WES of adult intellectual disabilities with co-morbid psychiatric disorders (2019-08-07)

  ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66-72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-08-07.

  Dataset EGAD00001005236

• Hofer et al., A specific subpopulation of cancer-associated fibroblasts promotes resistance to chemotherapy in triple-negative breast cancer by upregulating G0S2 protein

  Chemotherapy is the standard of care for patients with triple-negative breast cancer (TNBC), but the mechanisms of chemoresistance remain poorly understood. Here, we investigated the role of cancer associated fibroblasts (CAFs) in the chemotherapy response of TNBC, by combining in vivo analyses of TNBC patients with ex vivo cancer modeling, using tumor-on-chip (ToC) technology. Transcriptomic analysis revealed that the proportion of a specific CAF population, the extracellular matrix-producing myofibroblasts (ECM-myCAFs), is reduced after chemotherapy in chemo-sensitive, but not in chemo-resistant TNBC patients. In ToC devices, primary ECM-myCAFs promoted TNBC cell survival under Doxorubicin and Paclitaxel treatment. The mechanism of chemoresistance was elucidated by using single-cell RNA sequencing, advanced cell imaging and functional assays: ECM-myCAFs upregulate the G0/G1 switch 2 (G0S2) protein in TNBC cells, via activation of SRC family kinases. Altogether, our work identifies G0S2 as a new player in CAF mediated chemotherapy resistance in TNBC.

  Study EGAS50000000886

• First datasets available in the Federated EGA Network

  In February 2024, a great milestone was reached for the human omics data community: the first datasets are now available in the Federated European Genome-phenome Archive (FEGA). These datasets - hosted by national nodes in Poland, Norway, and Sweden - are discoverable in the EGA portal and accessible according to national laws. These datasets include: From FEGA Poland - The Genomic Map Of Poland From FEGA Norway - CRCbiome: Gut metagenome of Norwegian screening participants using FIT sampling Also from FEGA Norway - Single cell transcriptomics in expanded Tregs of APS-1 patients From FEGA Sweden - A Combined Omics and Tissue Biobank for Paediatric Cancers The establishment of these datasets represents a significant step towards achieving the broader objectives of the FEGA; to facilitate the sharing of high-quality human genomic and phenotypic data across borders. “The value for users is twofold: it becomes easier to make data available securely compared to storing data locally, and data becomes easier to find for other researchers. The possibility of reuse improves the chances of both verifying scientific discoveries and reaching groundbreaking conclusions, of benefit to the research community and later also patients,” said Anna Hagwall, project manager and head of human data at FEGA Sweden, NBIS. About Federated EGA FEGA was launched in 2022 as a network to store and lawfully share sensitive human omics data safely. It relies on the technology originally developed by the EGA and support from ongoing collaborations with ELIXIR - a European life sciences infrastructure. FEGA has contributed to and benefitted from the implementation of community standards for sensitive data management including those developed by the Global Alliance for Genomics and Health (GA4GH). “The FEGA concept and the development of the Nordic FEGA nodes have been made possible thanks to several projects coordinated by NeIC,” said Kjell Petersen, FEGA Norway technical lead. Managing human omics data is challenging due to its sheer size and privacy concerns, often resulting in restrictions on how and where sensitive data can be shared. The FEGA network follows a federated data access model whereby sensitive data is stored securely within a local or national jurisdiction, while discovery across the network for data of interest is enabled via a central portal. As of February 2024, the FEGA network comprises seven European national nodes with tens of additional national partners working towards establishing a FEGA node. As the FEGA network continues to onboard nodes from around the world, populated with more and more data, we move closer to a vision of a truly global resource for discovery of and access to sensitive human omics data to accelerate disease research and improve human health. "The Federated EGA network is entering a key phase where the first research datasets are now available across the network. In coming years, we look forward to expanding these datasets to cover key areas such as cancer and rare diseases for the benefit of patients" said Thomas Keane, Group Leader at EMBL-EBI.

  Blog first-datasets-available-in-Federated-EGA