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Perry, J.R.* ; Hsu, Y.H.* ; Chasman, D.I.* ; Johnson, A.D.* ; Elks, C.E.* ; Albrecht, E. ; Andrulis, I.L.* ; Beesley, J.* ; Berenson, G.S.* ; Bergmann, S.* ; Bojesen, S.E.* ; Bolla, M.K.* ; Brown, J.* ; Buring, J.E.* ; Campbell, H.* ; Chang-Claude, J.* ; Chenevix-Trench, G.* ; Corre, T.* ; Couch, F.J.* ; Cox, A.* ; Czene, K.* ; d'Adamo, A.P.* ; Davies, G.* ; Deary, I.J.* ; Dennis, J.* ; Easton, D.F.* ; Engelhardt, E.G.* ; Eriksson, J.G.* ; Esko, T.* ; Fasching, P.A.* ; Figueroa, J.D.* ; Flyger, H.* ; Fraser, A.* ; Garcia-Closas, M.* ; Gasparini, P.* ; Gieger, C. ; Giles, G.G.* ; Guénel, P.* ; Hägg, S.* ; Hall, P.* ; Hayward, C.* ; Hopper, J.L.* ; Ingelsson, E.* ; kConFab Investigators () ; Kardia, S.L.* ; Kasiman, K.* ; Knight, J.A.* ; Lahti, J.* ; Lawlor, D.A.* ; Magnusson, P.K.* ; Margolin, S.* ; Marsh, J.A.* ; Metspalu, A.* ; Olson, J.E.* ; Pennell, C.E.* ; Polasek, O.* ; Rahman, I.* ; Ridker, P.M.* ; Robino, A.* ; Rudan, I.* ; Rudolph, A.* ; Salumets, A.* ; Schmidt, M.K.* ; Schoemaker, M.J.* ; Smith, E.N.* ; Smith, J.A.* ; Southey, M.* ; Stöckl, D. ; Swerdlow, A.J.* ; Thompson, D.J.* ; Truong, T.* ; Ulivi, S.* ; Waldenberger, M. ; Wang, Q.* ; Wild, S.* ; Wilson, J.F.* ; Wright, A.F.* ; Zgaga, L.* ; RepoGen Consortium (*) ; Ong, K.K.* ; Murabito, J.M.* ; Karasik, D.* ; Murray, A.*

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

Hum. Mol. Genet. 23, 2490-2497 (2014)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Secular Trends; Premature Menopause; Reproductive Life; Menarche; Women; Cancer; Brca1; Association; Mutations; Cohort
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 23, Issue: 9, Pages: 2490-2497 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
G-504000-006
G-504091-001
PubMed ID 24357391
DOI 10.1093/hmg/ddt620
WOS ID WOS:000334359100022
Scopus ID 84897501936
Erfassungsdatum 2014-01-20
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