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Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry

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dc.contributor Háskóli Íslands
dc.contributor University of Iceland
dc.contributor.author Sapkota, Yadav
dc.contributor.author De Vivo, Immaculata
dc.contributor.author Steinthorsdottir, Valgerdur
dc.contributor.author Fassbender, Amelie
dc.contributor.author Bowdler, Lisa
dc.contributor.author Buring, Julie E.
dc.contributor.author Edwards, Todd L.
dc.contributor.author Jones, Sarah
dc.contributor.author Dorien, O.
dc.contributor.author Peterse, Danielle
dc.contributor.author Rexrode, Kathryn M.
dc.contributor.author Ridker, Paul M.
dc.contributor.author Schork, Andrew J.
dc.contributor.author Thorleifsson, Gudmar
dc.contributor.author Wallace, Leanne M.
dc.contributor.author Kraft, Peter
dc.contributor.author Morris, Andrew P.
dc.contributor.author Nyholt, Dale R.
dc.contributor.author Edwards, Digna R. Velez
dc.contributor.author Nyegaard, Mette
dc.contributor.author D'Hooghe, Thomas
dc.contributor.author Chasman, Daniel I.
dc.contributor.author Stefansson, Kari
dc.contributor.author Missmer, Stacey A.
dc.contributor.author Montgomery, Grant W.
dc.date.accessioned 2018-02-01T11:26:11Z
dc.date.available 2018-02-01T11:26:11Z
dc.date.issued 2017-09
dc.identifier.citation Sapkota, Y., Vivo, I. D., Steinthorsdottir, V., Fassbender, A., Bowdler, L., Buring, J. E., . . . Montgomery, G. W. (2017). Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry. Scientific Reports, 7(1), 11380. doi:10.1038/s41598-017-10440-9
dc.identifier.issn 2045-2322
dc.identifier.uri https://hdl.handle.net/20.500.11815/555
dc.description.abstract Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10−9) in GREB1 at 2p25.1 — a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.
dc.description.sponsorship We would like to acknowledge all the study participants in the QIMR, LEUVEN, NHS2, BioVU, WGHS, iPSYCH, and deCODE endometriosis studies that provided an opportunity for the current study. We also thank many hospital directors and staff, gynaecologists, general practitioners and pathology services in Australia, Belgium, the USA, Denmark and Iceland who provided assistance with confirmation of diagnoses. The QIMR study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. Hawkins and S. Hawkins. D.R.N. was supported by an NHMRC Fellowship (613674) and ARC Future Fellowship (FT0991022) schemes. G.W.M. (339446, 619667) was supported by the NHMRC Fellowships Scheme. The iPSYCH study was funded by the Lundbeck Foundation, Denmark (R155–2014–1724). The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen. A.P.M is a Wellcome Trust Senior Fellow in Basic Biomedical Science (under award WT098017). The NHS2 is supported by the National Cancer Institute [UM1 CA176726] and the National Institute of Child Health and Human Development [HD57210], with funding for white blood cell processing and DNA extraction provided by the Wellcome Trust [WT084766].
dc.format.extent 11380
dc.language.iso en
dc.publisher Springer Nature
dc.relation.ispartofseries Scientific Reports;7
dc.rights info:eu-repo/semantics/openAccess
dc.subject Genetic markers
dc.subject Genome-wide association studies
dc.subject Legslímuflakk
dc.subject Erfðafræði
dc.subject Rannsóknir
dc.title Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry
dc.type info:eu-repo/semantics/article
dc.description.version Peer Reviewed
dc.identifier.journal Scientific Reports
dc.identifier.doi 10.1038/s41598-017-10440-9
dc.contributor.department Læknadeild (HÍ)
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)

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