Perry JR, Hsu YH, Chasman DI, Johnson AD, Elks C, Albrecht E, Andrulis IL, Beesley J, Berenson GS, Bergmann S, Bojesen SE, Bolla MK, Brown J, Buring JE, Campbell H, Chang-Claude J, Chenevix-Trench G, Corre T, Couch FJ, Cox A, Czene K, D'adamo AP, Davies G, Deary IJ, Dennis J, Easton DF, Engelhardt EG, Eriksson JG, Esko T, Fasching PA, Figueroa JD, Flyger H, Fraser A, Garcia-Closas M, Gasparini P, Gieger C, Giles G, Guenel P, Hägg S, Hall P, Hayward C, Hopper J, Ingelsson E, kConFab investigators , Kardia SL, Kasiman K, Knight JA, Lahti J, Lawlor DA, Magnusson PK, Margolin S, Marsh JA, Metspalu A, Olson JE, Pennell CE, Polasek O, Rahman I, Ridker PM, Robino A, Rudan I, Rudolph A, Salumets A, Schmidt MK, Schoemaker MJ, Smith EN, Smith JA, Southey M, Stöckl D, Swerdlow AJ, Thompson DJ, Truong T, Ulivi S, Waldenberger M, Wang Q, Wild S, Wilson JF, Wright AF, Zgaga L, ReproGen Consortium , Ong KK, Murabito JM, Karasik D, Murray A
Hum. Mol. Genet. 23 (9) 2490-2497 [2014-05-01; online 2013-12-19]
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.