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DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

2013; Oxford University Press; Volume: 23; Issue: 9 Linguagem: Inglês

10.1093/hmg/ddt620

1460-2083

John R. B. Perry, Yi-Hsiang Hsu, Daniel I. Chasman, Andrew D. Johnson, Cathy E. Elks, Eva Albrecht, Irene L. Andrulis, Jonathan Beesley, Gerald S. Berenson, Sven Bergmann, Stig E. Bojesen, Manjeet K. Bolla, Judith Brown, Julie E. Buring, Harry Campbell, Jenny Chang‐Claude, Georgia Chenevix‐Trench, Tanguy Corre, Fergus J. Couch, Angela Cox, Kamila Czene, Pio D’Adamo, Gail Davies, Ian J. Deary, Joe Dennis, Douglas F. Easton, Ellen G. Engelhardt, Johan G. Eriksson, Tõnu Esko, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Abigail Fraser, Montserrat García‐Closas, Paolo Gasparini, Christian Gieger, Graham G. Giles, Pascal Guénel, Sara Hägg, Per Hall, Caroline Hayward, John L. Hopper, Erik Ingelsson, Sharon L. R. Kardia, Katherine Kasiman, Julia A. Knight, Jari Lahti, Debbie A. Lawlor, Patrik K. E. Magnusson, Sara Margolin, Julie Marsh, Andres Metspalu, Janet E. Olson, Craig E. Pennell, Ozren Polašek, Iffat Rahman, Paul M. Ridker, Antonietta Robino, Igor Rudan, Anja Rudolph, Andres Salumets, Marjanka K. Schmidt, Minouk J. Schoemaker, Erin N. Smith, Jennifer A. Smith, Melissa C. Southey, Doris Stöckl, Anthony J. Swerdlow, Deborah J. Thompson, Thérèse Truong, Sheila Ulivi, Mélanie Waldenberger, Qin Wang, Sarah H. Wild, James F. Wilson, Alan F. Wright, Lina Zgaga, Ken K. Ong, Joanne M. Murabito, David Karasik, Anna Murray,

Digestive system and related health

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.