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Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to 370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain 7.4% of the population variance in age at menarche, corresponding to 25% of the estimated heritability. We implicate 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

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Figure 1: GTEx tissue enrichment using LD score regression.
Figure 2: Stronger effects of AAM-associated signals on early menarche than late menarche in women.
Figure 3: Effects and 95% confidence intervals of genetically predicted AAM on risks for various sex-steroid-sensitive cancers, adjusted for the effects of the same AAM variants on BMI.

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Acknowledgements

This research has been conducted using the UK Biobank Resource under applications 5122 and 9797. Full study-specific acknowledgments can be found in the Supplementary Note.

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All authors reviewed the original and revised manuscripts. Statistical analysis: F.R.D., D.J.T., H.H., D.I.C., H.F., P.S., K.S.R., S.W., A.K.S., E. Albrecht, E. Altmaier, M.A., C.M.B., T. Boutin, A. Campbell, E.D., A.G., C. He, J.J.H., R.K., I.K., P.-R.L., K.L.L., M.M., B.M., G.M., S.E.M., I.M.N., R.N., T.N., L.P., N. Perjakova, E.P., L.M.R., K.E.S., A.V. Segrè, A.V. Smith, L.S., A.T., J.R.B.P. Sample collection, genotyping and phenotyping: I.L.A., S. Bandinelli, M.W.B., J.B., S. Bergmann, M.B., E.B., S.E.B., M.K.B., J.S.B., H. Brauch, H. Brenner, L.B., T. Brüning, J.E.B., H.C., E.C., S.C., G.C.-T., T.C., F.J.C., D.L.C., A. Cox, L.C., K.C., G.D.S., E.J.C.N.d., R.d., I.D.V., J.D., P.D., I.d.-S.-S., A.M.D., J.G.E., P.A.F., L.F.-R., L. Ferrucci, D.F.-J., L. Franke, M.G., I.G., G.G.G., H.G., D.F.G., P.G., P.H., E.H., U.H., T.B.H., C.A.H., G.H., M.J.H., J.L.H., F.H., D.J.H., H.K.I., M.-R.J., P.K.J., D.K., Z.K., G.L., D.L., C.L., L.J.L., J.S.E.L., S. Lenarduzzi, J. Li, P.A.L., S. Lindstrom, Y.L., J. Luan, R.M., A. Mannermaa, H.M., M.I.M., C. Meisinger, T.M., C. Menni, A. Metspalu, K.M., L.M., R.L.M., G.W.M., A.M.M., M.A.N., P.N., H.N., D.R.N., A.J.O., T.A.O., S.P., A. Palotie, N. Pedersen, A. Peters, J.P., P.D.P.P., A. Pouta, P.R., I. Rahman, S.M.R., A.R., F.R.R., I. Rudan, R.R., D.R., C.F.S., M.K.S., R.A.S., M. Shah, R.S., M.C.S., U.S., M. Stampfer, M. Steri, K. Strauch, T. Tanaka, E.T., N.J.T., M.T., T. Truong, J.P.T., A.G.U., D.R.V.E., V.V., U.V., P.V., Q.W., E.W., K.W.v.D., G.W., R.W., B.H.R.W., J.H.Z., M. Zoledziewska, M. Zygmunt. Individual study principal investigators: B.Z.A., D.I.B., M.C., F.C., T.E., N.F., C.G., V.G., C. Hayward, P.K., D.A.L., P.K.E.M., N.G.M., D.O.M.-K., E.A.N., O.P., D.P., A.L.P., P.M.R., H.S., T.D.S., D.S., D.T., S.U., J.A.V., H.V., N.J.W., J.F.W., A.B.S., U.T., K.S.P., D.F.E., J.Y.T., J.C.-C., D.H., A. Murray, J.M.M., K. Stefansson, K.K.O., J.R.B.P. Working group: F.R.D., D.J.T., H.H., D.I.C., H.F., P.S., K.S.R., S.W., A.K.S., A.B.S., U.T., K.S.P., D.F.E., J.Y.T., J.C., D.H., A. Murray, J.M.M., K. Stefansson, K.K.O., J.R.B.P.

Corresponding authors

Correspondence to Ken K Ong or John R B Perry.

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The authors declare no competing financial interests.

Additional information

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.

Integrated supplementary information

Supplementary Figure 1 Manhattan plot displaying the genomic locations of the 389 genome-wide significant loci.

Previously identified genome-wide significant loci are shown in gold, and new loci are shown in purple. SNPs within 300 kb of the lead SNP at each locus are highlighted. The y axis has been truncated above 30.

Supplementary Figure 2 Number of genome-wide significant menarche loci per chromosome by chromosome size.

The X chromosome is highlighted in red.

Supplementary Figure 3 Quantile–quantile plot of heterogeneity P values between maternal and paternal parent-of-origin association testing for all 389 index variants.

Supplementary Figure 4 LocusZoom plots of menarche-associated variants at the MKRN3 locus (hg38) in the deCODE study, Iceland.

The 5′ UTR variant rs530324840 at position chr15:23565461 is labeled as a diamond and shown in purple; other variants are colored according to correlation (r2) with rs530324840 (see legends). –log10 P values are shown along the left y axis, and the right y axis corresponds to recombination rate, plotted as a solid gray line. (a) Associations under the paternal model, where the signal near 24 Mb corresponds to the common reported variant rs12148769. (b) Associations under the maternal model. (c) Associations under the additive model.

Supplementary Figure 5 LocusZoom plots of menarche-associated variants at the DLK1 locus (hg38) in the deCODE study, Iceland.

The variant rs138827001 at position chr14:100771634 is labeled as a diamond and shown in purple; other variants are colored according to correlation (r2) with rs138827001 (see legends). –log10 P values are shown along the left y axis, and the right y axis corresponds to recombination rate, plotted as a solid gray line. (a) Associations under the paternal model. (b) Associations under the maternal model. (c) Associations under the additive model.

Supplementary Figure 6 Association of menarche-associated variants with adult body mass index.

The blue bars (and left y axis) indicate the collective variance explained in adult BMI (with bootstrap-generated 95% CIs) by index menarche-associated SNPs grouped by their individual associations with BMI (in UK Biobank using an additive model controlling for chip and principal components). The red line (and right y axis) indicates the –log10 P value for the collective association with BMI of each group of SNPs. Purple squares correspond to collective associations with BMI at P < 0.05.

Supplementary Figure 7 Dose-response plots for Mendelian randomization analyses.

(ad) The individual effects on AAM of the 314 ‘BMI-unrelated’ autosomal AAM variants are plotted against risks for breast (a), prostate (b), endometrial (c) and ovarian (d) cancer. Red line, IVW regression; blue line, MR-Egger regression. MR-Egger supports the protective effect of later age at puberty on breast, prostate and endometrial cancers, but indicates pleiotropy in the association with ovarian cancer.

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Day, F., Thompson, D., Helgason, H. et al. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. Nat Genet 49, 834–841 (2017). https://doi.org/10.1038/ng.3841

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