biostudies-literaturePerry JRCancer Research UKNIA NIH HHSMedical Research CouncilChief Scientist OfficeNCI NIH HHSNIAMS NIH HHSNational Breast Cancer FoundationWellcome TrustBiotechnology and Biological Sciences Research Council2490-7https://www.ebi.ac.uk/biostudies/studies/S-EPMC3976329biostudies-literatureUnknown23(9)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.Human molecular geneticsDNA mismatch repair gene MSH6 implicated in determining age at natural menopause.PMC3976329092447/Z/10/ZBB/F019394/1CZB/4/710165630701594MR/K026992/1R01 AG016592MC_UU_12013/5R21 AR056405MC_U106179472MC_UU_12015/2R01 CA12897810118G060070511022G0700704MC_PC_U127561128IF-12-06Flyger HZgaga LGarcia-Closas MUlivi SAndrulis ILJohnson ADReproGen ConsortiumPennell CEGuenel PFraser AWilson JFChasman DIGasparini PMurray ADeary IJSalumets ASwerdlow AJWang QEaston DFCouch FJChenevix-Trench GD'adamo APKasiman KLahti JHayward CThompson DJBolla MKHsu YHGieger CSchoemaker MJEsko TChang-Claude JBuring JEWright AFRahman ICorre TBerenson GSRobino AFasching PAEriksson JGHall PElks CSchmidt MKLawlor DAOng KKBeesley JStockl DDavies GTruong TBergmann SMurabito JMRudolph AKardia SLPolasek OWaldenberger MKarasik DIngelsson EHagg SFigueroa JDSmith ENAlbrecht EBojesen SEGiles GSmith JAPerry JRHopper JRidker PMCzene KRudan IKnight JAMargolin SMetspalu AMarsh JASouthey MCox AEngelhardt EGDennis JMagnusson PKOlson JECampbell HWild SBrown JkConFab investigatorsfalseDNA mismatch repair gene MSH6 implicated in determining age at natural menopause.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.2014-01-01T00:00:00Z2014 May2021-02-19T19:17:02Z2019-03-27T01:24:26ZS-EPMC39763292435739110.1093/hmg/ddt620