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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.

Original publication

DOI

10.1038/ng.3412

Type

Journal article

Journal

Nat Genet

Publication Date

11/2015

Volume

47

Pages

1294 - 1303

Keywords

Adult, Age Factors, Aging, BRCA1 Protein, Breast Neoplasms, DNA Repair, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomics, Genotype, Humans, Hypothalamus, Menopause, Middle Aged, Models, Genetic, Phenotype, Reproduction, Signal Transduction