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

Journal

Book Volume: 23

Pages Range: 2490-7

Journal Issue: 9

DOI: 10.1093/hmg/ddt620

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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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

MLA:

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.

BibTeX: Download