Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

被引：288

作者：

Stolk, Lisette ^{[2
,3
]}

Perry, John R. B. ^{[1
,4
]}

Chasman, Daniel I. ^{[5
,6
]}

He, Chunyan ^{[7
,8
]}

Mangino, Massimo ^{[9
]}

Sulem, Patrick ^{[10
]}

Barbalic, Maja ^{[11
]}

Broer, Linda ^{[12
]}

Byrne, Enda M.

Ernst, Florian ^{[14
]}

Esko, Tonu ^{[15
,16
,17
]}

Franceschini, Nora ^{[18
]}

Gudbjartsson, Daniel F. ^{[10
]}

Hottenga, Jouke-Jan ^{[19
]}

Kraft, Peter ^{[20
,21
,22
]}

McArdle, Patrick F. ^{[23
]}

Porcu, Eleonora ^{[24
]}

Shin, So-Youn ^{[25
]}

Smith, Albert V. ^{[26
,27
]}

van Wingerden, Sophie ^{[12
]}

Zhai, Guangju ^{[9
,28
]}

Zhuang, Wei V. ^{[29
]}

Albrecht, Eva ^{[30
]}

Alizadeh, Behrooz Z. ^{[31
]}

Aspelund, Thor ^{[26
,27
]}

Bandinelli, Stefania ^{[32
]}

Lauc, Lovorka Barac ^{[33
]}

Beckmann, Jacques S. ^{[34
,35
]}

Boban, Mladen ^{[36
]}

Boerwinkle, Eric ^{[11
]}

Broekmans, Frank J. ^{[37
]}

Burri, Andrea ^{[9
]}

Campbell, Harry ^{[38
]}

Chanock, Stephen J. ^{[39
]}

Chen, Constance ^{[20
,40
]}

Cornelis, Marilyn C. ^{[40
]}

Corre, Tanguy ^{[41
]}

Coviello, Andrea D. ^{[42
,43
]}

d'Adamo, Pio ^{[44
,45
]}

Davies, Gail ^{[46
]}

de Faire, Ulf ^{[47
]}

de Geus, Eco J. C. ^{[19
,48
]}

Deary, Ian J. ^{[46
,49
]}

Dedoussis, George V. Z. ^{[50
]}

Deloukas, Panagiotis ^{[25
]}

Ebrahim, Shah ^{[51
]}

Eiriksdottir, Gudny ^{[26
]}

Emilsson, Valur ^{[26
]}

Eriksson, Johan G. ^{[52
,53
,54
,55
,56
]}

Fauser, Bart C. J. M. ^{[37
]}

机构：

[1] Univ Exeter, Peninsula Med Sch, Exeter, Devon, England

[2] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[3] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands

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

[5] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA USA

[7] Indiana Univ Sch Med, Dept Publ Hlth, Indianapolis, IN USA

[8] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA

[9] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[10] deCODE Genet, Reykjavik, Iceland

[11] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX USA

[12] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[13] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia

[14] Ernst Moritz Arndt Univ Greifswald, Interfakultares Inst Genomforsch, Greifswald, Germany

[15] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[16] Estonian Bioctr, Tartu, Estonia

[17] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[18] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA

[19] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[20] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[21] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA

[22] MIT, Cambridge, MA 02139 USA

[23] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[24] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[25] Wellcome Trust Sanger Inst, Hinxton, England

[26] Iceland Heart Assoc, Kopavogur, Iceland

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

[28] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF, Canada

[29] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[30] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany

[31] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 AB Groningen, Netherlands

[32] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy

[33] Croatian Sci Fdn, Zagreb, Croatia

[34] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland

[35] Univ Lausanne Hosp, CHU Vaudois, Serv Med Genet, Lausanne, Switzerland

[36] Univ Split, Fac Med, Split, Croatia

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

[38] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[39] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[40] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[41] Ist Sci San Raffaele, Div Genet & Cell Biol, I-20132 Milan, Italy

[42] Boston Univ, Sch Med, Dept Med, Sect Gen Internal Med Prevent Med & Epidemiol, Boston, MA 02118 USA

[43] NHLBI, Framingham Heart Study, Framingham, MA USA

[44] Ist Ricovero & Cura Carattere Sci Materno Infanti, Inst Maternal & Child Hlth, Trieste, Italy

[45] Univ Trieste, Trieste, Italy

[46] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[47] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[48] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands

[49] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[50] Harokopio Univ, Dept Nutr & Dietet, Athens, Greece

来源：

NATURE GENETICS | 2012年 / 44卷 / 03期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

FOLLICLE-STIMULATING-HORMONE; PREMATURE OVARIAN FAILURE; GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; ONSET; POLYMORPHISMS; MUTATION; HERITABILITY; CHROMOSOME; MENARCHE;

D O I：

10.1038/ng.1051

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappa B signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

引用

页码：260 / U55

页数：11

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