Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

被引：291

作者：

Day, Felix R. ^{[1
]}

Ruth, Katherine S. ^{[2
]}

Thompson, Deborah J. ^{[3
]}

Lunetta, Kathryn L. ^{[4
,5
,6
]}

Pervjakova, Natalia ^{[7
,8
]}

Chasman, Daniel I. ^{[9
,10
]}

Stolk, Lisette ^{[11
,12
,13
]}

Finucane, Hilary K. ^{[14
,15
]}

Sulem, Patrick ^{[16
]}

Bulik-Sullivan, Brendan ^{[17
,18
,19
]}

Esko, Tonu ^{[7
,20
,21
,22
]}

Johnson, Andrew D. ^{[5
,6
]}

Elks, Cathy E. ^{[1
]}

Franceschini, Nora ^{[23
]}

He, Chunyan ^{[24
,25
]}

Altmaier, Elisabeth ^{[26
,27
]}

Brody, Jennifer A. ^{[28
]}

Franke, Lude L. ^{[29
]}

Huffman, Jennifer E. ^{[5
,6
,30
]}

Keller, Margaux F. ^{[31
]}

McArdle, Patrick F. ^{[32
]}

Nutile, Teresa ^{[33
]}

Porcu, Eleonora ^{[34
,35
,36
]}

Robino, Antonietta ^{[37
]}

Rose, Lynda M. ^{[9
]}

Schick, Ursula M. ^{[38
]}

Smith, Jennifer A. ^{[39
]}

Teumer, Alexander ^{[40
]}

Traglia, Michela ^{[41
]}

Vuckovic, Dragana ^{[37
,42
]}

Yao, Jie ^{[43
]}

Zhao, Wei ^{[39
]}

Albrecht, Eva ^{[27
]}

Amin, Najaf ^{[44
]}

Corre, Tanguy ^{[45
,46
]}

Hottenga, Jouke-Jan ^{[47
]}

Mangino, Massimo ^{[48
,49
]}

Smith, Albert V. ^{[50
,51
]}

Tanaka, Toshiko ^{[52
]}

Abecasis, Goncalo R. ^{[36
]}

Andrulis, Irene L. ^{[53
,54
]}

Anton-Culver, Hoda ^{[55
]}

Antoniou, Antonis C. ^{[3
]}

Arndt, Volker ^{[56
]}

Arnold, Alice M. ^{[57
]}

Barbieri, Caterina ^{[37
,41
]}

Beckmann, Matthias W. ^{[58
]}

Beeghly-Fadiel, Alicia ^{[59
]}

Benitez, Javier ^{[60
,61
]}

Bernstein, Leslie ^{[62
]}

机构：

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

[2] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England

[3] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

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

[5] NHLBI, Framingham, MA USA

[6] Boston Univ, Framingham Heart Study, Framingham, MA USA

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

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

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

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

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

[12] Netherlands Consortium Hlth Aging, Leiden, Netherlands

[13] Natl Genom Initiat, Leiden, Netherlands

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

[15] MIT, Dept Math, Cambridge, MA 02139 USA

[16] deCODE Genet Amgen Inc, Reykjavik, Iceland

[17] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA

[18] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[19] Broad Inst, Med & Populat Genet, Cambridge, MA USA

[20] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[21] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[22] Broad Inst MIT & Harvard, Cambridge, MA USA

[23] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[24] Indiana Univ, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46204 USA

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

[26] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany

[27] Helmholtz Zenntrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany

[28] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[29] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[30] Univ Edinburgh, Human Genet Unit, MRC, Inst Genet & Mol Med, Edinburgh EH8 9YL, Midlothian, Scotland

[31] Merck Pharmaceut, Boston, MA USA

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

[33] CNR, Inst Genet & Biophys, Naples, Italy

[34] CNR, Inst Genet & Biomed Res, Cagliari, Italy

[35] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy

[36] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[37] Sci Inst Res Hospitalisat & Hlth Care Burlo Garof, Inst Maternal & Child Hlth, Trieste, Italy

[38] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[39] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[40] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

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

[42] Univ Trieste, Dept Clin Med Sci Surg & Hlth, Trieste, Italy

[43] Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, LABioMed, Torrance, CA 90509 USA

[44] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands

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

[46] Swiss Inst Bioinformat, Lausanne, Switzerland

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

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

[49] Guys & St Thomas Fdn Trust, Biomed Res Ctr, Natl Inst Hlth Res, London, England

[50] Icelandic Heart Assoc, Kopavogur, Iceland

来源：

NATURE GENETICS | 2015年 / 47卷 / 11期

关键词：

OVARIAN FAILURE; HOMOLOGOUS RECOMBINATION; NATURAL MENOPAUSE; WIDE ASSOCIATION; CELL-TYPES; BRCA1; LOCI; AGE; RECEPTOR; INSUFFICIENCY;

D O I：

10.1038/ng.3412

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

引用

页码：1294 / +

页数：12

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