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

Perry JRB, 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 P, Figueroa JD, Flyger H, Fraser A, Garcia-Closas M, Gasparini P, Gieger C, Giles G, Guenel P, Haegg S, Hall P, Hayward C, Hopper J, Ingelsson E, Kardia LR, Kasiman K, Knight JA, Lahti J, Lawlor DA, Magnusson PKE, 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, Stoeckl D, Swerdlow AJ, Thompson DJ, Truong T, Ulivi S, Waldenberger M, Wang Q, Wild S, Wilson JF, Wright AF, Zgaga L, Ong KK, Murabito JM, Karasik D, Murray A (2014)

Publication Type: Journal article

Publication year: 2014


Book Volume: 23

Pages Range: 2490-7

Journal Issue: 9

DOI: 10.1093/hmg/ddt620


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.

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Involved external institutions

University of Exeter GB United Kingdom (GB) Institute for Aging Research US United States (USA) (US) Harvard University US United States (USA) (US) US National Institutes of Health (NIH) US United States (USA) (US) Addenbrooke's Hospital GB United Kingdom (GB) Mount Sinai Hospital (MSH) CA Canada (CA) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Tulane University US United States (USA) (US) Université de Lausanne (UNIL) CH Switzerland (CH) Copenhagen University Hospital DK Denmark (DK) University of Cambridge GB United Kingdom (GB) University of Edinburgh GB United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Mayo Clinic US United States (USA) (US) University of Sheffield GB United Kingdom (GB) Karolinska Institute SE Sweden (SE) Università degli Studi di Trieste IT Italy (IT) Netherlands Cancer Institute (NKI) NL Netherlands (NL) Helsingin yliopisto / University of Helsinki FI Finland (FI) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Boston Children's Hospital US United States (USA) (US) National Cancer Institute (NCI) US United States (USA) (US) University of Bristol GB United Kingdom (GB) The University of Melbourne AU Australia (AU) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) FR France (FR) Uppsala University SE Sweden (SE) University of Michigan US United States (USA) (US) Folkhälsan Research Center FI Finland (FI) University of Western Australia (UWA) AU Australia (AU) University of Tartu EE Estonia (EE) University of Split / Sveučilište u Splitu HR Croatia (HR) University of California, San Diego US United States (USA) (US) I.R.C.C.S. materno infantile Burlo Garofolo IT Italy (IT)

How to cite


Perry, J.R.B., Hsu, Y.-H., Chasman, D.I., Johnson, A.D., Elks, C., Albrecht, E.,... Murray, A. (2014). DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Human Molecular Genetics, 23(9), 2490-7. https://doi.org/10.1093/hmg/ddt620


Perry, John R. B., et al. "DNA mismatch repair gene MSH6 implicated in determining age at natural menopause." Human Molecular Genetics 23.9 (2014): 2490-7.

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