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

John R B Perry, Yi-Hsiang Hsu, Daniel I Chasman, Cathy Elks, Eva Albrecht, Irene L Andrulis, Jonathan Beesley, Gerald S Berenson, Sven Bergmann, Stig E Bojesen, Manjeet K Bolla, Julie E Buring, Harry Campbell, Jenny Chang-Claude, Georgia Chenevix-Trench, Tanguy Corre, Fergus J Couch, Angela Cox, Kamila Czene, Adamo Pio D'adamoGail 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, Debbie A Lawlor, kConFab investigators

Research output: Contribution to journalArticle (Academic Journal)peer-review

27 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2490-7
Number of pages8
JournalHuman Molecular Genetics
Volume23
Issue number9
DOIs
Publication statusPublished - 1 May 2014

Keywords

  • Age Factors
  • DNA-Binding Proteins
  • Female
  • Genome-Wide Association Study
  • Humans
  • Menopause
  • Polymorphism, Single Nucleotide

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