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 atmenarche andmenopause, but to date theknowngenes 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, wefoundnorobust 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.
Bibliographical noteFunding Information:
J.R.B.P is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). D.A.L. and A.F. work in a centre that receives infrastructure funding from the UK Medical Research Council (G0600705) and A.F. is funded by a UK Medical Research Council Post-doctoral research fellowship (0701594). Further information on funding for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.