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

Human Molecular Genetics
John R B PerryAnna Murray

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.

References

Jun 17, 1998·The Journal of Clinical Endocrinology and Metabolism·H SniederT D Spector
Mar 21, 2001·Human Molecular Genetics·P Peltomäki
Dec 13, 2001·American Journal of Human Genetics·Maran J W BerendsJan H Kleibeuker
May 28, 2004·Nature·Aleksandra TrifunovicNils-Göran Larsson
Jun 15, 2005·Annual Review of Biochemistry·Thomas A Kunkel, Dorothy A Erie
Sep 10, 2005·Best Practice & Research. Clinical Endocrinology & Metabolism·David B DungerKen K Ong
Mar 29, 2006·International Journal of Obesity : Journal of the International Association for the Study of Obesity·W WangH-W Deng
Jun 15, 2006·Breast Cancer Research and Treatment·Izabella Rzepka-GórskaAleksandra Tołoczko-Grabarek
Aug 25, 2006·American Journal of Epidemiology·Hazel B NicholsPolly A Newcomb
Mar 25, 2008·American Journal of Epidemiology·Katherine DeLellis HendersonMalcolm C Pike
Nov 26, 2008·The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine·M Anne HarrisMieke Koehoorn
May 28, 2009·Nature Genetics·Patricia Hartge
Jul 31, 2009·American Journal of Human Biology : the Official Journal of the Human Biology Council·Roxana MoslehiJan M Friedman
Dec 10, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kutluk OktaySamir N Babayev
Oct 12, 2010·Nature Genetics·Elizabeth K SpeliotesRuth J F Loos
Dec 21, 2010·American Journal of Human Genetics·Jian YangPeter M Visscher
Jun 9, 2011·Paediatric and Perinatal Epidemiology·Danielle H MorrisAnthony J Swerdlow
Dec 5, 2012·PLoS Genetics·Ke HaoDon D Sin
Feb 7, 2013·Journal of the National Cancer Institute·Aung Ko WinMark A Jenkins
Feb 15, 2013·Science Translational Medicine·Shiny TitusKutluk Oktay
Feb 19, 2013·Fertility and Sterility·Amy FinchUNKNOWN Hereditary Breast Cancer Study Group

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Citations

Jan 8, 2016·Journal of Zhejiang University. Science. B·Min-hao HuFan Jin
Mar 23, 2015·Fertility and Sterility·Kerem Wainer-KatsirMichal Linial
Jun 1, 2016·Fertility and Sterility·Daniel M T FesslerRicardo Azziz
Sep 14, 2016·Maturitas·Joop S E LavenJan H J Hoeijmakers
Aug 23, 2016·Fertility and Sterility·Erika T Chow, Shruthi Mahalingaiah
Jan 30, 2018·Frontiers in Oncology·Robin L AndersonKara L Britt
Apr 9, 2019·Journal of the Royal Society, Interface·Joseph BerleantErik Winfree
Jun 13, 2017·Frontiers in Oncology·Genevieve Victoria Dall, Kara Louise Britt
Nov 30, 2019·BioMed Research International·Xiaoyu XiYanzhi Jiang
Dec 1, 2020·Circulation·Samar R El KhoudaryUNKNOWN American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardio
Feb 12, 2021·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Hideki InnanReiner A Veitia
Mar 2, 2021·Seminars in Reproductive Medicine·Joop S E Laven
Jul 8, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Qingling YangAaron J Hsueh

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Methods Mentioned

BETA
hysterectomy

Software Mentioned

GCTA
METAL
eLC
eLX package

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