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

John R.B. Perry, Yi Hsiang Hsu, Daniel I. Chasman, Andrew D. Johnson, Cathy 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 CoxKamila Czene, Adamo 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, Montse Garcia-Closas, Paolo Gasparini, Christian Gieger, Graham Giles, Pascal Guenel, Sara Hägg, Per Hall, Caroline Hayward, John Hopper, Erik Ingelsson, Sharon L.R. Kardia, Katherine Kasiman, Julia A. Knight, Jari Lahti, Debbie A. Lawlor, Patrik K.E. Magnusson, Sara Margolin, Julie A. Marsh, Andres Metspalu, Janet E. Olson, Craig E. Pennell, Ozren Polasek, 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 Southey, Doris Stöckl, Anthony J. Swerdlow, Deborah J. Thompson, Therese Truong, Sheila Ulivi, Melanie Waldenberger, Qin Wang, Sarah Wild, James F. Wilson, Alan F. Wright, Lina Zgaga, Ken K. Ong, Joanne M. Murabito, David Karasik, Anna Murray

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numberddt620
Pages (from-to)2490-2497
Number of pages8
JournalHuman molecular genetics
Volume23
Issue number9
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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