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; Guðmar Þorleifsson; 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; Gudmar Thorleifsson

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, Guðmar Þorleifsson, 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, Gudmar Thorleifsson

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109 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
Number of pages	15539
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15539
Publication status	Published - 24 May 2017

Other keywords

Genetic variation
Genetics research
Genome-wide association studies
Risk factors
Erfðabreytileiki
Erfðafræði
Áhættuþættir
Rannsóknir
Legslímuflakk
Gen
OAG12
Endometriosis
Genes
Genetic Loci

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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., ... Thorleifsson, G. (2017). Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nature Communications, 8. https://doi.org/10.1038/ncomms15539

@article{5582d1718caf46f4a9260ae312471296,

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.",

keywords = "Genetic variation, Genetics research, Genome-wide association studies, Risk factors, Erf{\dh}abreytileiki, Erf{\dh}afr{\ae}{\dh}i, {\'A}h{\ae}ttu{\th}{\ae}ttir, Ranns{\'o}knir, Legsl{\'i}muflakk, Gen, OAG12, Endometriosis, Genes, Genetic Loci, Genetic variation, Genetics research, Genome-wide association studies, Risk factors, Erf{\dh}abreytileiki, Erf{\dh}afr{\ae}{\dh}i, {\'A}h{\ae}ttu{\th}{\ae}ttir, Ranns{\'o}knir, Legsl{\'i}muflakk, Gen, OAG12, Endometriosis, Genes, Genetic Loci",

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 Gu{\dh}mar {\TH}orleifsson 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 Siew-Kee Low 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.} and Gudmar Thorleifsson",

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, Þorleifsson, G, Geirsson, RT , Thorsteinsdottir, U, Wallace, LM, Werge, TM, Thompson, WK, Yang, J, Velez Edwards, DR, Nyegaard, M, Low, S-K, Zondervan, KT, Missmer, SA, D'Hooghe, T, Montgomery, GW, Chasman, DI, Stefansson, K, Tung, JY, Nyholt, DR & Thorleifsson, G 2017, 'Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism', Nature Communications, vol. 8. 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 - Þorleifsson, Guðmar

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.

AU - Thorleifsson, Gudmar

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.

KW - Genetic variation

KW - Genetics research

KW - Genome-wide association studies

KW - Risk factors

KW - Erfðabreytileiki

KW - Erfðafræði

KW - Áhættuþættir

KW - Rannsóknir

KW - Legslímuflakk

KW - Gen

KW - OAG12

KW - Endometriosis

KW - Genes

KW - Genetic Loci

KW - Genetic variation

KW - Genetics research

KW - Genome-wide association studies

KW - Risk factors

KW - Erfðabreytileiki

KW - Erfðafræði

KW - Áhættuþættir

KW - Rannsóknir

KW - Legslímuflakk

KW - Gen

KW - OAG12

KW - Endometriosis

KW - Genes

KW - Genetic Loci

U2 - 10.1038/ncomms15539

DO - 10.1038/ncomms15539

M3 - Article

C2 - 28537267

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

Other keywords

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