Abstract
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
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A full list of acknowledgements can be found in the Supplementary Information.
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Overall project management: J.R.B.P., F.D., C.E.E., P.S., D.J.T., D.F.E., K.S., J.M.M. and K.K.O. Core analyses: J.R.B.P., F.D., C.E.E., P.S., T.F., D.J.T., D.I.C. and T.E. Individual study analysts: A.A.R., A.D., A.G., A.J., A.T., A.V.S., B.Z.A., B.F., C.E.E., D.F.G., D.I.C., D.J.T., D.L.C., D.L.K., E.A., E.K.W., E.M., E.M.B., E.T., F.D., G.M., G.McMahon, I.M.N., J.A.V., J.D., J.H., J.R.B.P., J.T., J.Z., K.L.L., K.M., L.L.P., L.M.R., L.M.Y., L.S., M.M., N.F., N.Ts., P.K., P.S., R.M., S.K., S.S., S.S.U., T.C., T.E., T.F., T.Fo., T.H.P., W.Q.A. and Z.K. Individual study data management and generation: A.A.R., A.C.H., A.D., A.D.C., A.G.U., A.J.O., A.M.S., A.Mu., A.P., A.Po., B.A.O., C.A.H., D.C., D.I.C., D.J.H., D.K., D.Lw., D.P.K., D.P.S., D.S., E.A.N., E.P., E.W., F.A., F.B.H., F.G., F.R., G.D., G.E., G.G.W., H.S., H.W., I.D., J.C., J.H., J.P.R., L.F., L.Fr., L.M., L.M.R., M.E.G., M.J.S., M.J.W., M.K.B., M.Melbye, M.P., M.W., N.A., N.J.T., N.L.P., P.K.M., Q.W., R.H., S.B., S.C., S.G., S.L., S.R., S.S.U., T.E., U.S., U.T., V.S. and W.L.M. Individual study principal investigators: A.C., A.G.U., A.H., A.J.O., A.K.D., A.L., A.M., A.M.D., A.Mannermaa, A.Mu., A.R., B.B., B.Z.A., B.H.R.W., C.B., C.E.P., C.G., C.H., C.van Duijn, D.I.B., D.F., D.F.E., D.J.H., D.L., D.Lw., D.S.P., D.P.S., D.Schlessinger, E.A.S., E.B., E.E.J.d.G., E.I., E.W., E.W.D., F.B.H., F.J.C., G.C., G.D., G.G.G., G.Wa., G.Wi., G.W.M., H.A., H.A.B., H.B., H.Be., H.F., H.N., H.S., H.V., I.D., I.L.A., J.A.K., J.B., J.C.C., J.G.E., J.E.B., J.L.H., J.M.C., J.M.M., J.P., K.C., K.K., K.K.O., K.P., K.S., L.C., L.F., L.J.B., M.C.S., M.G., M.I.M., M.J., M.J.E., M.J.H., M.J.S., M.K.S., M.W.B., M.Z., N.G.M., N.J.W., P.A.F., P.D., P.D.P.P., P.F.M., P.G., P.H., P.K., P.M.R., P.N., P.P., P.P.G., P.R., P.V., R.J.F.L., R.L.M., R.W., S.B., S.Bergmann, S.C., S.E.B., T.B.H., T.D.S., T.I.A.S., U.H., V.G., V.K. and V.S.
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Additional information
Plots of all 106 menarche loci and genome-wide summary level statistics are available at the ReproGen Consortium website: http://www.reprogen.org.
Extended data figures and tables
Extended Data Figure 2 Estimates of genetic variance explained.
Variance in age at menarche in the EPIC-InterAct replication sample (N = 8,689) explained by combined sets of SNPs defined by their strength of association in the discovery set.
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1-5 and 8 and 9. (PDF 1373 kb)
Supplementary Data
This file contains Supplementary Tables 6 and 7. (XLSX 323 kb)
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Perry, J., Day, F., Elks, C. et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514, 92–97 (2014). https://doi.org/10.1038/nature13545
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DOI: https://doi.org/10.1038/nature13545
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