期刊
NATURE GENETICS
卷 47, 期 11, 页码 1294-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.3412
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资金
- MRC [MC_UU_12015/1, MC_UU_12015/2, MC_PC_U127561128, MC_U106179472] Funding Source: UKRI
- Cancer Foundation Finland sr [130168] Funding Source: researchfish
- Cancer Research UK [16565, 11174, 16459, 15007, 16563, 16561, 17528] Funding Source: researchfish
- Chief Scientist Office [CZD/16/6/4, CZB/4/710] Funding Source: researchfish
- Medical Research Council [MC_UU_12015/2, MC_UU_12015/1, 1233641, MC_PC_U127561128, MC_U106179472, MC_PC_13048, MC_U106179471] Funding Source: researchfish
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10135, NF-SI-0514-10027, 03/DHCS/03/G121/51] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10124] Funding Source: researchfish
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.
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