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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

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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Figure 1: Manhattan and quantile–quantile plot of the GWAS for age at menarche.
Figure 2: Forest plot of parent-of-origin-specific allelic associations at three imprinted menarche loci.
Figure 3

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Acknowledgements

A full list of acknowledgements can be found in the Supplementary Information.

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Contributions

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.

Corresponding authors

Correspondence to John R. B. Perry or Joanne M. Murabito.

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Competing interests

The authors declare no competing financial interests.

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 1 Flow chart illustrating the selection criteria used to identify independent signals for age at menarche.

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.

Extended Data Table 1 Details of the 123 independent signals for menarche timing at 106 genomic loci—signals no. 1 to 30
Extended Data Table 2 Details of the 123 independent signals for menarche timing at 106 genomic loci—signals no. 31 to 58
Extended Data Table 3 Details of the 123 independent signals for menarche timing at 106 genomic loci—signals no. 59 to 87
Extended Data Table 4 Details of the 123 independent signals for menarche timing at 106 genomic loci—signals no. 88 to 106
Extended Data Table 5 Methylation QTLs based on Illumina 450K whole blood and adipose methylome data in 648 twins
Extended Data Table 6 MAGENTA pathway analyses
Extended Data Table 7 GABAB receptor II signalling pathway genes

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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