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

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.

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Figure 1: Miami plot of HapMap and exome SNP associations.
Figure 2: Multiple signals at HELB and relationship to DNA helicase B protein sequence.
Figure 3: Classification of the genes identified as being involved in DDR pathways at genetic loci associated with ANM.

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Acknowledgements

For full acknowledgments, see the Supplementary Note.

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All authors reviewed the original and revised manuscripts. Statistical analysis: F.R.D., K.S.R., D.J.T., K.L.L., N.P., D.I.C., L.S., H.K.F., P.S., B.B.-S., T.E., A.D.J., C.E.E., N.F., C. He, E. Altmaier, J.A.B., L.L.F., J.E.H., S.E.J., M.F.K., P.F.M., T.N., E.P., A. Robino, L.M.R., U.M.S., J.A.S., A.T., M.T., D. Vuckovic, J.Y., W. Zhao, E. Albrecht, N.A., T.C., J.-J.H., M.M., A.V.S., T. Tanaka, J.R.B.P. Sample collection, genotyping and phenotyping: G.R.A., I.L.A., H.A.-C., A.C.A., V.A., A.M.A., C. Barbieri, M.W.B., A.B.-F., J.B., L.B., S.J.B., C. Blomqvist, E.B., N.V.B., S.E.B., M.K.B., A.-L.B.-D., T.S.B., H. Brauch, H. Brenner, T.B., B.B., A. Campbell, H.C., S.J.C., J.R.C., Y.-D.I.C., G.C.-T., F.J.C., A.D.C., A. Cox, K.C., H.D., I.D.V., E.W.D., J.D., P.D., T.D., I.d.-S.-S., A.M.D., J.D.E., P.A.F., J.D.F., J.F., D.F.-J., I.G., M.E.G., M.G.-C., G.G. Giles, G.G. Girotto, M.S.G., A.G.-N., M.O.G., M.L.G., D.F.G., P.G., X.G., C.A.H., P.H., U.H., B.E.H., L.J.H., A.H., G.H., M.J.H., J.L.H., F.B.H., J.H., K.H., D.J.H., A.J., M.K., D.K., J.A.K., I.K., C.K., V.-M.K., J.K., V.K., D.L., C.L., J. Li, X.L., S.L., Y.L., J. Luan, J. Lubinski, R.M., A. Mannermaa, J. Manz, S.M., J. Marten, N.G.M., C.M., A. Meindl, K.M., E.M., L.M., R.L.M., M.M.-N., M.N., B.M.N., H.N., P.N., A.B.N., B.G.N., J.E.O., S.P., P.P., U.P., A. Petersmann, J.P., P.D.P.P., N.N.P., A. Pirie, G.P., O.P., D.P., B.M.P., K.P., P.R., L.J.R., F.R., I.R., A. Rudolph, D.R., C.F.S., S.S., E.J.S., D. Schlessinger, M.K.S., F.S., R.K.S., M.J.S., R.A.S., C.M.S., J.S., R.S., M.C.S., D. Stöckl, K. Strauch, A.S., K.D.T., U.T., A.E.T., I.T., T. Truong, L.T., S.T.T., D. Vozzi, Q.W., M.W., G.W., J.F.W., R.W., B.B.H.R.W., A.F.W., D.Y., T.Z., W. Zheng, M.Z. Individual study principal investigators: S.B., D.I.B., J.E.B., L.F., G.W.M., V.G., T.D.S., C.M.v.D., B.Z.A., M.C., L.C., D.F.E., P.P.G., C.G., T.B.H., C. Hayward, S.L.R.K., P.K., B.M., A. Metspalu, A.C.M., A.P.R., P.M.R., J.I.R., D.T., A.G.U., S.U., H.V., N.J.W., D.R.W., L.M.Y.-A., A.L.P., K. Stefansson, J.A.V., K.K.O., J.C.-C., J.M.M., A. Murray. Working group: F.R.D., K.S.R., D.J.T., K.L.L., N.P., D.I.C., L.S., H.K.F., P.S., B.B.-S., T.E., A.D.J., C.E.E., N.F., C. He, A.L.P., K. Stefansson, J.A.V., K.K.O., J.C.-C., J.M.M., J.R.B.P., A. Murray.

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Correspondence to John R B Perry.

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A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

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Day, F., Ruth, K., Thompson, D. et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 47, 1294–1303 (2015). https://doi.org/10.1038/ng.3412

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