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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

Abstract

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10−8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

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Figure 1: Discovery GWAS results.

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Acknowledgements

We are grateful to the study participants and staff from all cohorts involved in this study. Extended acknowledgments per cohort are in Supplementary Note.

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Individual study design and management were done by D.I.C., C. He, E.M.B., P.K., J.S.B., M. Boban, E.B., H.C., S.J.C., U.d.F., I.J.D., G.V.Z.D., S.E., J.G.E., L. Ferrucci, A.R.F., P.G., C.J.M.W.G., C.G., D.E.G., P.H., S.E.H., A.H., E.I., S.L.R.K., D.A.L., P.K.E.M., M. Marongiu, N.G.M., V.M., N.C.O.-M., G. Paré, A.N.P., N.L.P., P.H.M.P., O.P., B.M.P., K.R., I.R., J.M.S., R.P.S., V.J.M.P., V.G., G.E., T.B.H., L.J.L.,Y.V.S., A.T., Y.T.v.d.S., P.M.V., G. Waeber, H.E.W., J.F.W., B.H.R.W., L.M.L., D.I.B., J.E.B., L.C., F.B.H., D.J.H., G.W.M., B.A.O., P.M.R., D.S., T.D.S., K. Stefansson, E.A.S., M.U., C.M.v.D., H.V., S.B., A. Salumets and A. Metspalu. Data collection was done by B.Z.A., S.B., L.B.L., J.S.B., M. Boban, A.B., H.C., P.dA., U.dF., I.J.D., G.V.Z.D., S.E., J.G.E., L. Ferreli, L. Ferrucci, A.R.F., D.E.G., P.H., S.E.H., A.C.H., A.H., A.C.J.W.J., I.K., S.L., D.A.L., P.K.E.M., N.G.M., I.M.K., A.B.N., N.L.P., P.H.M.P., O.P., B.M.P., K.R., I.R., A. Scuteri, S.N.S., J.M.S., M.G.S., U.S., B.T., L.T., S.U., V.J.M.P., V.G., G.E., Y.T.v.d.S., C.H.v.G., J.M.V., G. Waeber, H.E.W., A.F.W., T.Z., L.Z., M.C.Z., M.Z., L.M.L., A.M.A., J.E.B., E.A.S., A.G.U., J.M.M., P.v.N. and A. Metspalu. Genotyping was done by J.K., L.S., T.E., E.B., F.J.B., S.J.C., P.dA., G.D., P.D., C. Hayward, A.C.H., J. Liu, B.C.J.M.F., S.E.M., V.M., P.N., D.R.N., N.C.O.-M., A.S.P., A.N.P., B.M.P., J.I.R., A. Singleton, K. Stirrups, A.T., K.T., Y.T.v.d.S., M.V., E.W., T.Z., L.M.L., F.B.H., G.W.M., B.A.O. and U.T. Genotype preparation was done by J.R.B.P., M. Barbalic, N.F., E.P., S.-Y.S., W.V.Z., L.B.L., P.dA., G.D., C.J.M.W.G., C.G., C. Hayward, E.I., S.L.R.K., P.K.E.M., I.M.K., C.M., S.E.M., P.N., D.R.N., N.C.O.-M., A.P., G. Pistis, E.R., C.S., J.A.S., H.S., N.S., Y.V.S., A.T., M.V., E.W., T.Z., L.M.L., F.B.H., D.J.H., S.S., K.L.L. and M.H. Phenotype preparation was done by J.R.B.P., L.S., C. He, M. Mangino, M. Barbalic, L.B., E.M.B., F.E., N.F., D.F.G., J.-J.H., P.K., G.Z., W.V.Z., L.B.L., M. Boban, E.J.C.d.G., I.J.D., G.V.Z.D., M.G.S., S.E., J.G.E., C.H.v.G., L. Ferreli, K.F., M.H., C. Hayward, E.I., A.C.J.W.J., S.L.R.K., I.K., J. Lahti, S.L., T.L., D.A.L., L.M.L., P.K.E.M., I.M.K., C.M., P.H.M.P., G. Pistis, O.P., E.R., C.S., A. Scuteri, J.A.S., B.T., S.U., R.M.v.D., V.G., G.E., T.A., Y.T.v.d.S., H.W., G. Willemsen, B.H.R.W., A.F.W., M.C.Z., L.M.L., A.M.A., E.W.D., A. Metspalu, K.L.L. and J.M.M. Analysis plan development was done by L.S., D.I.C., C. He, E.M.B., P.K., T.C., P.G., D.K., D.P.K., N.G.M., D.T., D.J.H., G.W.M., K.L.L., J.M.M. and A. Murray. Analysis plan review was done by L.S., D.I.C., C. He, A.V.S., A.D.C., N.G., D.K., D.P.K., B.M., A.B.N., B.M.P., A.M.A., D.J.H., K.L.L., J.M.M. and A. Murray. Study data analysis was done by L.S., D.I.C., C. He, M. Mangino, M. Barbalic, L.B., E.M.B., F.E., T.E., N.F., D.F.G., J.-J.H., P.K., P.F.M., E.P., S.-Y.S., A.V.S., S.v.W., G.Z., W.V.Z., E.A., C.C., M.C.C., T.C., N.G., T.H., C. Hayward, Z.K., J. Lahti, D.A.L., L.M.L., D.M., N.C.O.M., G. Paré, G. Pistis, A.S.P., V.E., E.R., J.A.S., M.G.S., S.U., Y.T.vdS., M.V., L.M.Y.-A., L.Z., S.S. and U.T. Review and interpretation of analyses were done by J.R.B.P., L.S., D.I.C., C. He, P.S., M. Barbalic, E.M.B., N.F., P.K., P.F.M., A.V.S., B.Z.A., S.J.C., A.D.C., I.J.D., S.E.H., E.I., D.K., S.L.R.K., D.P.K., L.M.L., P.K.E.M., N.G.M., G. Paré, A.S.P., J.A.S., H.S., L.M.Y.-A., J.E.B., E.W.D., F.B.H., D.J.H., G.W.M., P.M.R., C.M.v.D., H.V., K.L.L., J.M.M., P.v.N. and A. Murray. Meta-analyses were done by L.S., P.S. and K.L.L. Pathway and other analyses were done by J.R.B.P., D.I.C., C. He, A.D.J., M. Mangino, G. Paré and J.A.V. Menopause study was designed by J.R.B.P., L.S., D.I.C., C. He, D.E.G., P.H.M.P., Y.T.v.d.S., C.H.v.G., A. Metspalu, K.L.L., J.M.M. and A. Murray. Manuscript was prepared by J.R.B.P., L.S., D.I.C., C. He, T.E., N.F., A.D.C., D.K., D.P.K., E.W.D., A. Metspalu, K.L.L., J.M.M., A. Murray and J.A.V. Manuscript was reviewed by J.R.B.P., L.S., D.I.C., C. He, N.F., P.K., P.F.M., A.V.S., B.Z.A., T.A., L.B.L., J.S.B., M. Boban, F.J.B., H.C., S.J.C., C.C., M.C.C., A.D.C., G.D., U.d.F., I.J.D., G.E., B.C.J.M.F., M.E.G., N.G., D.E.G., P.H., S.E.H., C. Hayward, E.I., D.K., D.P.K., S.L.R.K., J.A.S., I.K., Z.K., T.L., T.E., A. Salumets, A. Metspalu, J.S.E.L., J. Liu, L.M.L., Y.V.L., P.K.E.M., I.M.K., B.M., V.M., P.N., A.B.N., N.C.O.-M., G. Paré, A.N.P., N.L.P., P.H.M.P., O.P., B.M.P., J.I.R., I.R., H.S., J.M.S., R.P.S., A.T., R.M.v.D., Y.T.v.d.S., C.H.v.G., P.M.V., M.V., G. Waeber, J.F.W., B.H.R.W., A.F.W., L.M.Y.-A., T.Z., L.Z., M.C.Z., V.J.M.P., L.M.L., A.M.A., D.I.B., J.E.B., E.W.D., V.G., T.B.H., F.B.H., D.J.H., L.J.L., P.M.R., T.D.S., E.A.S., H.V., K.L.L., J.M.M., A. Murray, P.v.N. and J.A.V. Consortium was overseen by K.L.L., J.M.M., A. Murray and J.A.V.

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Correspondence to Anna Murray or Kathryn L Lunetta.

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Competing interests

V.M. was a full-time employee of GlaxoSmithKline when this work was done. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetical order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. F.J.B. is a member of the external advisory board for Merck Serono, does consultancy work for MSD and carries out educational activities for Ferring. B.M.P. discloses (i) service on a data and safety monitoring board for a clinical trial of a device funded by the manufacturer and (ii) service on the steering committee for the Yale Open-Data Project, which is funded by Medtronic for the review of clinical trial data on recombinant morphogenic protein 2.

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Stolk, L., Perry, J., Chasman, D. et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 44, 260–268 (2012). https://doi.org/10.1038/ng.1051

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