Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

Sapkota, Yadav; Steinthorsdottir, Valgerdur; Morris, Andrew P.; Fassbender, Amelie; Rahmioglu, Nilufer; De Vivo, Immaculata; Buring, Julie E.; Zhang, Futao; Edwards, Todd L.; Jones, Sarah; O, Dorien; Peterse, Daniëlle; Rexrode, Kathryn M.; Ridker, Paul M.; Schork, Andrew J.; MacGregor, Stuart; Martin, Nicholas G.; Becker, Christian M.; Adachi, Sosuke; Yoshihara, Kosuke; Enomoto, Takayuki; Takahashi, Atsushi; Kamatani, Yoichiro; Matsuda, Koichi; Kubo, Michiaki; Þorleifsson, Guðmar; Geirsson, Reynir T.; Thorsteinsdottir, Unnur; Wallace, Leanne M.; Werge, Thomas M.; Thompson, Wesley K.; Yang, Jian; Velez Edwards, Digna R.; Nyegaard, Mette; Low, Siew-Kee; Zondervan, Krina T.; Missmer, Stacey A.; D'Hooghe, Thomas; Montgomery, Grant W.; Chasman, Daniel I.; Stefansson, Kari; Tung, Joyce Y.; Nyholt, Dale R.

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dc.contributor	Háskóli Íslands
dc.contributor	University of Iceland
dc.contributor.author	Sapkota, Yadav
dc.contributor.author	orcid.org/0000-0003-1846-6274 Steinthorsdottir, Valgerdur
dc.contributor.author	Morris, Andrew P.
dc.contributor.author	Fassbender, Amelie
dc.contributor.author	Rahmioglu, Nilufer
dc.contributor.author	De Vivo, Immaculata
dc.contributor.author	Buring, Julie E.
dc.contributor.author	Zhang, Futao
dc.contributor.author	Edwards, Todd L.
dc.contributor.author	Jones, Sarah
dc.contributor.author	O, Dorien
dc.contributor.author	Peterse, Daniëlle
dc.contributor.author	Rexrode, Kathryn M.
dc.contributor.author	Ridker, Paul M.
dc.contributor.author	Schork, Andrew J.
dc.contributor.author	MacGregor, Stuart
dc.contributor.author	Martin, Nicholas G.
dc.contributor.author	Becker, Christian M.
dc.contributor.author	Adachi, Sosuke
dc.contributor.author	Yoshihara, Kosuke
dc.contributor.author	Enomoto, Takayuki
dc.contributor.author	Takahashi, Atsushi
dc.contributor.author	Kamatani, Yoichiro
dc.contributor.author	Matsuda, Koichi
dc.contributor.author	Kubo, Michiaki
dc.contributor.author	Þorleifsson, Guðmar
dc.contributor.author	Geirsson, Reynir T.
dc.contributor.author	Thorsteinsdottir, Unnur
dc.contributor.author	Wallace, Leanne M.
dc.contributor.author	Werge, Thomas M.
dc.contributor.author	Thompson, Wesley K.
dc.contributor.author	Yang, Jian
dc.contributor.author	Velez Edwards, Digna R.
dc.contributor.author	Nyegaard, Mette
dc.contributor.author	Low, Siew-Kee
dc.contributor.author	Zondervan, Krina T.
dc.contributor.author	Missmer, Stacey A.
dc.contributor.author	D'Hooghe, Thomas
dc.contributor.author	Montgomery, Grant W.
dc.contributor.author	Chasman, Daniel I.
dc.contributor.author	orcid.org/0000-0003-1676-864X Stefansson, Kari
dc.contributor.author	Tung, Joyce Y.
dc.contributor.author	Nyholt, Dale R.
dc.date.accessioned	2017-07-19T13:28:45Z
dc.date.available	2017-07-19T13:28:45Z
dc.date.issued	2017-05-24
dc.identifier.citation	Sapkota, Y., Steinthorsdottir, V., Morris, A. P., Fassbender, A., Rahmioglu, N., De Vivo, I., . . . Nyholt, D. R. (2017). Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. 8, 15539. doi:10.1038/ncomms15539
dc.identifier.issn	2041-1723
dc.identifier.uri	https://hdl.handle.net/20.500.11815/342
dc.description.abstract	Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10−8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.
dc.description.sponsorship	We acknowledge all the study participants in 11 individual 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 who provided assistance with confirmation of diagnoses. We would like to thank the research participants and employees of 23andMe for making this work possible. We thank the subjects of the Icelandic deCODE study for their participation. We thank research staff and clinicians for providing diagnostic confirmation for the OX data set. We would like to express our gratitude to the staff and members of the Biobank Japan and Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences for their outstanding assistance. The QIMR study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241,944, 339,462, 389,927, 389,875, 389,891, 389,892, 389,938, 443,036, 442,915, 442,981, 496,610, 496,739, 552,485, 552,498, 1,026,033 and 1,050,208), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne) and donations from N. Hawkins and S. Hawkins. Analyses of the QIMRHCS and OX GWAS were supported by the Wellcome Trust (WT084766/Z/08/Z) and makes use of WTCCC2 control data generated by the Wellcome Trust Case-Control Consortium (awards 076113 and 085475). The iPSYCH study was funded by The Lundbeck Foundation, Denmark (R102-A9118, R155-2014-1724 ), and the research has been conducted using the Danish National Biobank resource supported by the Novo Nordisk Foundation. A full list of the investigators who contributed to the generation of these data is available from http://www.wtccc.org.uk. D.R.N. was supported in part by the NHMRC Fellowship (613674) and ARC Future Fellowship (FT0991022) schemes. E.G.H. (631096) and G.W.M. (339446, 619667) were supported by the NHMRC Fellowships Scheme. S.M. is supported by an Australian Research Council Future Fellowship. A.P.M. was supported by a Wellcome Trust Senior Research Fellowship (award WT098017). N.R. was supported by funding from the Medical Research Council UK (MR/K011480/1). This study was funded by the BioBank Japan project, which is supported by the Ministry of Education, Culture, Sports, Sciences and Technology of Japanese government.
dc.format.extent	15539
dc.language.iso	en
dc.publisher	Springer Nature
dc.relation.ispartofseries	Nature Communications;8
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Genetic variation
dc.subject	Genetics research
dc.subject	Genome-wide association studies
dc.subject	Risk factors
dc.subject	Erfðabreytileiki
dc.subject	Erfðafræði
dc.subject	Áhættuþættir
dc.subject	Rannsóknir
dc.title	Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism
dc.type	info:eu-repo/semantics/article
dcterms.license	This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
dc.description.version	Peer Reviewed
dc.identifier.journal	Nature Communications
dc.identifier.doi	10.1038/ncomms15539
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)