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Loci at chromosomes 13, 19 and 20 influence age at natural menopause


We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 × 10−11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10−11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10−8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

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Figure 1: Meta-analysis of risk for early menopause (<50 years) by genotype for the six genome-wide-significant hits.

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This study was funded by the European Commision (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008-35627, TREAT-OA), Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS-database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. TwinsUK is supported by the Wellcome Trust from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. The LASA study is largely funded by the Ministry of Health, Welfare and Sports of The Netherlands. The PROSPECT-Frailty study was funded by The Netherlands Organization for Health Research and Development (ZON) no. 2100.0011.

We thank K. Lunetta for helpful discussion. The authors are very grateful to the study participants and staff from the Rotterdam Study and the TwinsUK, EPOS, PROSPECT-Frailty and LASA studies.

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L.S., G.Z., T.D.S. and A.G.U. designed the study. L.S. and M.M.P.J.V. did the genotyping of the replication studies. P.D. and N.S. did the genotyping for the TwinsUK study. N.S. did the quality control for the TwinsUK data. L.S., G.Z., J.B.J.v.M. and K.E. did the statistical analyses. L.S., G.Z., J.B.J.v.M., J.A.V., F.R., J.S.E.L., T.D.S. and A.G.U. helped with the interpretation of the results. L.S., G.Z., J.B.J.v.M., J.A.V., F.R., T.D.S. and A.G.U. prepared the manuscript and the revision of the manuscript. F.M.W., A.H. and H.A.P.P. critically revised the manuscript. A.H., J.W., H.A.P.P. and A.G.U. were involved in the sample and phenotype collection of the Rotterdam Study. F.M.W. and L.C. were involved in the phenotype collection of the TwinsUK Study. J.J.d.K., V.J.M.P., P.L., C.E.I.L., Y.T.v.d.S. and D.E.G. were involved in the sample and data collection of the replication studies.

Note: Supplementary information is available on the Nature Genetics website.

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Correspondence to André G Uitterlinden.

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L.S., G.Z., T.D.S. and A.G.U. are involved in a patent application based on the results of the work in this manuscript.

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Supplementary Note, Supplementary Tables 1–4, Supplementary Figures 1 and 2 and Supplementary Methods (PDF 550 kb)

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Stolk, L., Zhai, G., van Meurs, J. et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 41, 645–647 (2009).

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