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

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

doi:10.1038/ncomms15539

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

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

Research output: Contribution to journal › Article › peer-review

200 Citations (Scopus)

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.

Original language	English
Article number	15539
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15539
Publication status	Published - 24-05-2017
Externally published	Yes

All Science Journal Classification (ASJC) codes

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/ncomms15539

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Sapkota, Y., Steinthorsdottir, V., Morris, A. P., Fassbender, A., Rahmioglu, N., De Vivo, I., Buring, J. E., Zhang, F., Edwards, T. L., Jones, S., Dorien, O., Peterse, D., Rexrode, K. M., Ridker, P. M., Schork, A. J., MacGregor, S., Martin, N. G., Becker, C. M., Adachi, S., ... Nyholt, D. R. (2017). Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nature communications, 8, Article 15539. https://doi.org/10.1038/ncomms15539

@article{8027cc940155449c903fce56ecb43ed1,

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

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.",

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

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = may,

day = "24",

doi = "10.1038/ncomms15539",

language = "English",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Sapkota, Y, Steinthorsdottir, V, Morris, AP, Fassbender, A, Rahmioglu, N, De Vivo, I, Buring, JE, Zhang, F, Edwards, TL, Jones, S, Dorien, O, Peterse, D, Rexrode, KM, Ridker, PM, Schork, AJ, MacGregor, S, Martin, NG, Becker, CM, Adachi, S, Yoshihara, K, Enomoto, T, Takahashi, A, Kamatani, Y, Matsuda, K, Kubo, M, Thorleifsson, G, Geirsson, RT, Thorsteinsdottir, U, Wallace, LM, Werge, TM, Thompson, WK, Yang, J, Velez Edwards, DIR, Nyegaard, M, Low, SK, Zondervan, KT, Missmer, SA, D'Hooghe, T, Montgomery, GW, Chasman, DI, Stefansson, K, Tung, JY & Nyholt, DR 2017, 'Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism', Nature communications, vol. 8, 15539. https://doi.org/10.1038/ncomms15539

TY - JOUR

T1 - Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

AU - Sapkota, Yadav

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew P.

AU - Fassbender, Amelie

AU - Rahmioglu, Nilufer

AU - De Vivo, Immaculata

AU - Buring, Julie E.

AU - Zhang, Futao

AU - Edwards, Todd L.

AU - Jones, Sarah

AU - Dorien, O.

AU - Peterse, Daniëlle

AU - Rexrode, Kathryn M.

AU - Ridker, Paul M.

AU - Schork, Andrew J.

AU - MacGregor, Stuart

AU - Martin, Nicholas G.

AU - Becker, Christian M.

AU - Adachi, Sosuke

AU - Yoshihara, Kosuke

AU - Enomoto, Takayuki

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Matsuda, Koichi

AU - Kubo, Michiaki

AU - Thorleifsson, Gudmar

AU - Geirsson, Reynir T.

AU - Thorsteinsdottir, Unnur

AU - Wallace, Leanne M.

AU - Werge, Thomas M.

AU - Thompson, Wesley K.

AU - Yang, Jian

AU - Velez Edwards, DIgna R.

AU - Nyegaard, Mette

AU - Low, Siew Kee

AU - Zondervan, Krina T.

AU - Missmer, Stacey A.

AU - D'Hooghe, Thomas

AU - Montgomery, Grant W.

AU - Chasman, Daniel I.

AU - Stefansson, Kari

AU - Tung, Joyce Y.

AU - Nyholt, Dale R.

N1 - Funding Information: 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. Publisher Copyright: © 2017 The Author(s).

PY - 2017/5/24

Y1 - 2017/5/24

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms15539

DO - 10.1038/ncomms15539

M3 - Article

C2 - 28537267

AN - SCOPUS:85019935832

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 15539

ER -

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

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