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. 2014 May 1;23(9):2490-7.
doi: 10.1093/hmg/ddt620. Epub 2013 Dec 19.

DNA Mismatch Repair Gene MSH6 Implicated in Determining Age at Natural Menopause

Free PMC article

DNA Mismatch Repair Gene MSH6 Implicated in Determining Age at Natural Menopause

John R B Perry et al. Hum Mol Genet. .
Free PMC article


The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.


Figure 1.
Figure 1.
Regional plot illustrating the strength of association (−log10 P) versus hg19 position. The purple diamond represents the lead SNP in the combined analysis of replication and discovery data. Other dots, coloured according to the degree of pairwise linkage disequilibrium, represent single SNP test statistics for discovery stage only, including rs1800932, which was the SNP with lowest P value in the discovery analysis. The lower panels show structures of genes; layered ENCODE histone modification marks (H3K4Me1 which marks enhancers; H3K4Me3 which marks promoters and H3K27Ac which marks active regulatory regions) and linkage disequilibrium pairwise correlation (r2) derived from the CEU population in the 1000 Genomes Project, where white corresponds to r2 = 0 and black to r2 = 1.

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    1. Hartge P. Genetics of reproductive lifespan. Nat. Genet. 2009;41:637–638. - PubMed
    1. Elks C.E., Perry J.R., Sulem P., Chasman D.I., Franceschini N., He C., Lunetta K.L., Visser J.A., Byrne E.M., Cousminer D.L., et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 2010;42:1077–1085. - PMC - PubMed
    1. Stolk L., Perry J.R., Chasman D.I., He C., Mangino M., Sulem P., Barbalic M., Broer L., Byrne E.M., Ernst F., et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat. Genet. 2012;44:260–268. - PMC - PubMed
    1. van Noord P.A., Dubas J.S., Dorland M., Boersma H., te Velde E. Age at natural menopause in a population-based screening cohort: the role of menarche, fecundity, and lifestyle factors. Fertil. Steril. 1997;68:95–102. - PubMed
    1. Cooper G.S., Baird D.D., Darden F.R. Measures of menopausal status in relation to demographic, reproductive, and behavioral characteristics in a population-based study of women aged 35–49 years. Am. J. Epidemiol. 2001;153:1159–1165. - PubMed

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