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

Nat Genet
Authors
Keywords
Abstract

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 ∼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 (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Year of Publication
2015
Journal
Nat Genet
Volume
47
Issue
11
Pages
1294-303
Date Published
2015 Nov
ISSN
1546-1718
URL
DOI
10.1038/ng.3412
PubMed ID
26414677
PubMed Central ID
PMC4661791
Links
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N01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
CA128978 / CA / NCI NIH HHS / United States
HL054481 / HL / NHLBI NIH HHS / United States
HL043851 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
P30-DK072488 / DK / NIDDK NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
N.1-AG-1-2111 / AG / NIA NIH HHS / United States
C5047/A10692 / Cancer Research UK / United Kingdom
HHSN271201100004C / PHS HHS / United States
RC4 AG039029 / AG / NIA NIH HHS / United States
11174 / Cancer Research UK / United Kingdom
N01-AG-1-2109 / AG / NIA NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
HHSN268201100001C / PHS HHS / United States
R01-088119 / PHS HHS / United States
HHSN268201100005C / PHS HHS / United States
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N01AG62101 / AG / NIA NIH HHS / United States
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UL1 TR000124 / TR / NCATS NIH HHS / United States
1U19 CA148537 / CA / NCI NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
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MC_U106179471 / Medical Research Council / United Kingdom
C5047/A8384 / Cancer Research UK / United Kingdom
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C12292/A11174 / Cancer Research UK / United Kingdom
N01HC85081 / HC / NHLBI NIH HHS / United States
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MC_UU_12015/2 / Medical Research Council / United Kingdom
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MC_U106179472 / Medical Research Council / United Kingdom
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HL054464 / HL / NHLBI NIH HHS / United States
HL087660 / HL / NHLBI NIH HHS / United States
N.1-AG-1-1 / AG / NIA NIH HHS / United States
C8197/A16565 / Cancer Research UK / United Kingdom
RC2 AG036495 / AG / NIA NIH HHS / United States
HG006513 / HG / NHGRI NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
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C1287/A 10710 / Cancer Research UK / United Kingdom
N01-HC-95160 / HC / NHLBI NIH HHS / United States
CZD/16/6/4 / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
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HL054457 / HL / NHLBI NIH HHS / United States
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1U19 CA148112 / CA / NCI NIH HHS / United States
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C1281/A12014 / Cancer Research UK / United Kingdom
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HG007022 / HG / NHGRI NIH HHS / United States
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HG005581 / HG / NHGRI NIH HHS / United States
C1287/A10118 / Cancer Research UK / United Kingdom
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R21AG032598 / AG / NIA NIH HHS / United States
HHSN268201100006C / PHS HHS / United States
R01AG29451 / AG / NIA NIH HHS / United States
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AG023629 / AG / NIA NIH HHS / United States
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HG007089 / HG / NHGRI NIH HHS / United States
C5047/A15007 / Cancer Research UK / United Kingdom
10124 / Cancer Research UK / United Kingdom
K01-HL116770 / HL / NHLBI NIH HHS / United States