Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

被引：366

作者：

Day, Felix ^{[1
]}

Karaderi, Tugce ^{[2
,3
]}

Jones, Michelle R. ^{[4
]}

Meun, Cindy ^{[5
]}

He, Chunyan ^{[6
,7
]}

Drong, Alex ^{[2
]}

Kraft, Peter ^{[8
,9
]}

Lin, Nan ^{[6
,7
]}

Huang, Hongyan ^{[8
,9
]}

Broer, Linda ^{[10
]}

Magi, Reedik ^{[11
]}

Saxena, Richa ^{[12
]}

Laisk, Triin ^{[11
,13
]}

Urbanek, Margrit ^{[14
,15
]}

Hayes, M. Geoffrey ^{[14
,15
,16
]}

Thorleifsson, Gudmar ^{[17
]}

Fernandez-Tajes, Juan ^{[2
]}

Mahajan, Anubha ^{[2
,18
]}

Mullin, Benjamin H. ^{[19
,20
]}

Stuckey, Bronwyn G. A. ^{[19
,20
,21
]}

Spector, Timothy D. ^{[22
]}

Wilson, Scott G. ^{[19
,20
,22
]}

Goodarzi, Mark O. ^{[23
]}

Davis, Lea ^{[24
,25
]}

Obermayer-Pietsch, Barbara ^{[26
]}

Uitterlinden, Andre G. ^{[10
]}

Anttila, Verneri ^{[27
,28
,29
]}

Neale, Benjamin M. ^{[27
,28
,29
]}

Jarvelin, Marjo-Riitta ^{[30
,31
,32
,33
]}

Fauser, Bart ^{[34
]}

Kowalska, Irina ^{[35
]}

Visser, Jenny A. ^{[36
]}

Andersen, Marianne ^{[37
]}

Ong, Ken ^{[1
]}

Stener-Victorin, Elisabet ^{[38
]}

Ehrmann, David ^{[39
]}

Legro, Richard S. ^{[40
]}

Salumets, Andres ^{[13
,41
,42
,43
,44
]}

McCarthy, Mark I. ^{[2
,18
,45
]}

Morin-Papunen, Laure ^{[46
,47
]}

Thorsteinsdottir, Unnur ^{[17
,48
]}

Stefansson, Kari ^{[17
,48
]}

Styrkarsdottir, Unnur ^{[17
]}

Perry, John R. B. ^{[1
]}

Dunaif, Andrea ^{[14
,49
]}

Laven, Joop ^{[5
]}

Franks, Steve ^{[50
]}

Lindgren, Cecilia M. ^{[2
,12
,51
]}

Welt, Corrine K. ^{[52
,53
]}

机构：

[1] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Eastern Mediterranean Univ, Fac Arts & Sci, Dept Biol Sci, Gazimagusa, Cyprus

[4] Cedars Sinai Med Ctr, Dept Biomed Sci, Ctr Bioinformat & Funct Genom, Los Angeles, CA 90048 USA

[5] Univ Med Ctr Rotterdam, Erasmus MC, Dept Obstet & Gynaecol, Div Reprod Endocrinol & Infertil, Rotterdam, Netherlands

[6] Univ Kentucky, Coll Med, Dept Internal Med, Lexington, KY USA

[7] Univ Kentucky, Markey Canc Ctr, Lexington, KY USA

[8] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[9] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[10] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[11] Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia

[12] Harvard Med Sch, Broad Inst Harvard & MIT & Massachusetts Gen Hosp, Boston, MA 02115 USA

[13] Univ Tartu, Inst Clin Med, Dept Obstet & Gynaecol, Tartu, Estonia

[14] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA

[15] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA

[16] Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA

[17] Amgen Inc, DeCODE Genet, Reykjavik, Iceland

[18] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[19] Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA, Australia

[20] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia

[21] Keogh Inst Med Res, Nedlands, WA, Australia

[22] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[23] Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA

[24] Vanderbilt Univ, Med Ctr, Dept Med, Div Med Genet, Nashville, TN USA

[25] Vanderbilt Univ, Med Ctr, Vanderbilt Genom Inst, Nashville, TN USA

[26] Med Univ Graz, Dept Internal Med, Div Endocrinol & Diabetol, Graz, Austria

[27] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Genet, Cambridge, MA USA

[28] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[29] Harvard Med Sch, Boston, MA USA

[30] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England

[31] Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland

[32] Univ Oulu, Bioctr Oulu, Oulu, Finland

[33] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland

[34] Univ Med Ctr, Dept Reprod Med & Gynaecol, Utrecht, Netherlands

[35] Med Univ Bialystok, Dept Internal Med & Metab Dis, Bialystok, Poland

[36] Univ Med Ctr Rotterdam, Erasmus MC, Endocrinol Sect, Dept Internal Med, Rotterdam, Netherlands

[37] Univ Southern Denmark, Odense Univ Hosp, Odense, Denmark

[38] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden

[39] Univ Chicago, Dept Med, Sect Adult & Paediat Endocrinol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[40] Penn State Univ, Coll Med, Dept Obstet & Gynecol & Publ Hlth Sci, Hershey, PA USA

[41] Competence Ctr Hlth Technol, Tartu, Estonia

[42] Univ Tartu, Inst Bio & Translat Med, Tartu, Estonia

[43] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland

[44] Helsinki Univ Hosp, Helsinki, Finland

[45] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford, England

[46] Univ Oulu, Dept Obstet & Gynecol, Oulu, Finland

[47] Oulu Univ Hosp, Med Res Ctr, PEDEGO Res Unit, Oulu, Finland

[48] Univ Iceland, Fac Med, Reykjavik, Iceland

[49] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA

[50] Imperial Coll London, Dept Surg & Canc, Inst Reprod & Dev Biol, London, England

来源：

PLOS GENETICS | 2018年 / 14卷 / 12期

基金：

英国惠康基金; 欧盟第七框架计划; 欧盟地平线“2020”;

关键词：

SUSCEPTIBILITY LOCI; SYNDROME PCOS; ASSOCIATION; PREVALENCE; WOMEN; TWIN; RISK; HYPERANDROGENEMIA; IDENTIFICATION; PHENOTYPE;

D O I：

10.1371/journal.pgen.1007813

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

引用

页数：20

共 71 条

[1] A method and server for predicting damaging missense mutations [J].