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

John R.B. Perry; Yi Hsiang Hsu; Daniel I. Chasman; Andrew D. Johnson; Cathy Elks; Eva Albrecht; Irene L. Andrulis; Jonathan Beesley; Gerald S. Berenson; Sven Bergmann; Stig E. Bojesen; Manjeet K. Bolla; Judith Brown; Julie E. Buring; Harry Campbell; Jenny Chang-Claude; Georgia Chenevix-Trench; Tanguy Corre; Fergus J. Couch; Angela Cox; Kamila Czene; Adamo Pio D'adamo; Gail 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; Jari Lahti; Debbie A. Lawlor; Patrik K.E. Magnusson; Sara Margolin; Julie A. Marsh; Andres Metspalu; Janet E. Olson; Craig E. Pennell; Ozren Polasek; Iffat Rahman; Paul M. Ridker; Antonietta Robino; Igor Rudan; Anja Rudolph; Andres Salumets; Marjanka K. Schmidt; Minouk J. Schoemaker; Erin N. Smith; Jennifer A. Smith; Melissa Southey; Doris Stöckl; Anthony J. Swerdlow; Deborah J. Thompson; Therese Truong; Sheila Ulivi; Melanie Waldenberger; Qin Wang; Sarah Wild; James F. Wilson; Alan F. Wright; Lina Zgaga; Ken K. Ong; Joanne M. Murabito; David Karasik; Anna Murray

doi:10.1093/hmg/ddt620

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

John R.B. Perry, Yi Hsiang Hsu, Daniel I. Chasman, Andrew D. Johnson, Cathy Elks, Eva Albrecht, Irene L. Andrulis, Jonathan Beesley, Gerald S. Berenson, Sven Bergmann, Stig E. Bojesen, Manjeet K. Bolla, Judith Brown, Julie E. Buring, Harry Campbell, Jenny Chang-Claude, Georgia Chenevix-Trench, Tanguy Corre, Fergus J. Couch, Angela CoxKamila Czene, Adamo Pio D'adamo, Gail 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, Jari Lahti, Debbie A. Lawlor, Patrik K.E. Magnusson, Sara Margolin, Julie A. Marsh, Andres Metspalu, Janet E. Olson, Craig E. Pennell, Ozren Polasek, Iffat Rahman, Paul M. Ridker, Antonietta Robino, Igor Rudan, Anja Rudolph, Andres Salumets, Marjanka K. Schmidt, Minouk J. Schoemaker, Erin N. Smith, Jennifer A. Smith, Melissa Southey, Doris Stöckl, Anthony J. Swerdlow, Deborah J. Thompson, Therese Truong, Sheila Ulivi, Melanie Waldenberger, Qin Wang, Sarah Wild, James F. Wilson, Alan F. Wright, Lina Zgaga, Ken K. Ong, Joanne M. Murabito, David Karasik, Anna Murray

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

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 atmenarche andmenopause, but to date theknowngenes 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, wefoundnorobust 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 language	English
Article number	ddt620
Pages (from-to)	2490-2497
Number of pages	8
Journal	Human Molecular Genetics
Volume	23
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddt620
State	Published - May 2014
Externally published	Yes

Bibliographical note

Funding Information:
J.R.B.P is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). D.A.L. and A.F. work in a centre that receives infrastructure funding from the UK Medical Research Council (G0600705) and A.F. is funded by a UK Medical Research Council Post-doctoral research fellowship (0701594). Further information on funding for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

Funding

J.R.B.P is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). D.A.L. and A.F. work in a centre that receives infrastructure funding from the UK Medical Research Council (G0600705) and A.F. is funded by a UK Medical Research Council Post-doctoral research fellowship (0701594). Further information on funding for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

Funders	Funder number
National Institute on Aging	R01AG016592
Wellcome Trust
Medical Research Council	G0600705, 0701594

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddt620

Cite this

Perry, J. R. B., Hsu, Y. H., Chasman, D. I., Johnson, A. D., Elks, C., 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., ... Murray, A. (2014). DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Human Molecular Genetics, 23(9), 2490-2497. Article ddt620. https://doi.org/10.1093/hmg/ddt620

@article{735caec808f54049b66aa3892265ca61,

title = "DNA mismatch repair gene MSH6 implicated in determining age at natural menopause",

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 atmenarche andmenopause, but to date theknowngenes 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, wefoundnorobust 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.",

author = "Perry, {John R.B.} and Hsu, {Yi Hsiang} and Chasman, {Daniel I.} and Johnson, {Andrew D.} and Cathy Elks and Eva Albrecht and Andrulis, {Irene L.} and Jonathan Beesley and Berenson, {Gerald S.} and Sven Bergmann and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Judith Brown and Buring, {Julie E.} and Harry Campbell and Jenny Chang-Claude and Georgia Chenevix-Trench and Tanguy Corre and Couch, {Fergus J.} and Angela Cox and Kamila Czene and D'adamo, {Adamo Pio} and Gail Davies and Deary, {Ian J.} and Joe Dennis and Easton, {Douglas F.} and Engelhardt, {Ellen G.} and Eriksson, {Johan G.} and T{\~o}nu Esko and Fasching, {Peter A.} and Figueroa, {Jonine D.} and Henrik Flyger and Abigail Fraser and Montse Garcia-Closas and Paolo Gasparini and Christian Gieger and Graham Giles and Pascal Guenel and Sara H{\"a}gg and Per Hall and Caroline Hayward and John Hopper and Erik Ingelsson and Kardia, {Sharon L.R.} and Katherine Kasiman and Knight, {Julia A.} and Jari Lahti and Lawlor, {Debbie A.} and Magnusson, {Patrik K.E.} and Sara Margolin and Marsh, {Julie A.} and Andres Metspalu and Olson, {Janet E.} and Pennell, {Craig E.} and Ozren Polasek and Iffat Rahman and Ridker, {Paul M.} and Antonietta Robino and Igor Rudan and Anja Rudolph and Andres Salumets and Schmidt, {Marjanka K.} and Schoemaker, {Minouk J.} and Smith, {Erin N.} and Smith, {Jennifer A.} and Melissa Southey and Doris St{\"o}ckl and Swerdlow, {Anthony J.} and Thompson, {Deborah J.} and Therese Truong and Sheila Ulivi and Melanie Waldenberger and Qin Wang and Sarah Wild and Wilson, {James F.} and Wright, {Alan F.} and Lina Zgaga and Ong, {Ken K.} and Murabito, {Joanne M.} and David Karasik and Anna Murray",

note = "Funding Information: J.R.B.P is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). D.A.L. and A.F. work in a centre that receives infrastructure funding from the UK Medical Research Council (G0600705) and A.F. is funded by a UK Medical Research Council Post-doctoral research fellowship (0701594). Further information on funding for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.",

year = "2014",

month = may,

doi = "10.1093/hmg/ddt620",

language = "אנגלית",

volume = "23",

pages = "2490--2497",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

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, PA, Figueroa, JD, Flyger, H, Fraser, A, Garcia-Closas, M, Gasparini, P, Gieger, C, Giles, G, Guenel, P, Hägg, S, Hall, P, Hayward, C, Hopper, J, Ingelsson, E, Kardia, SLR, 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, Stöckl, 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, 'DNA mismatch repair gene MSH6 implicated in determining age at natural menopause', Human Molecular Genetics, vol. 23, no. 9, ddt620, pp. 2490-2497. https://doi.org/10.1093/hmg/ddt620

TY - JOUR

T1 - DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

AU - Perry, John R.B.

AU - Hsu, Yi Hsiang

AU - Chasman, Daniel I.

AU - Johnson, Andrew D.

AU - Elks, Cathy

AU - Albrecht, Eva

AU - Andrulis, Irene L.

AU - Beesley, Jonathan

AU - Berenson, Gerald S.

AU - Bergmann, Sven

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brown, Judith

AU - Buring, Julie E.

AU - Campbell, Harry

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Corre, Tanguy

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Czene, Kamila

AU - D'adamo, Adamo Pio

AU - Davies, Gail

AU - Deary, Ian J.

AU - Dennis, Joe

AU - Easton, Douglas F.

AU - Engelhardt, Ellen G.

AU - Eriksson, Johan G.

AU - Esko, Tõnu

AU - Fasching, Peter A.

AU - Figueroa, Jonine D.

AU - Flyger, Henrik

AU - Fraser, Abigail

AU - Garcia-Closas, Montse

AU - Gasparini, Paolo

AU - Gieger, Christian

AU - Giles, Graham

AU - Guenel, Pascal

AU - Hägg, Sara

AU - Hall, Per

AU - Hayward, Caroline

AU - Hopper, John

AU - Ingelsson, Erik

AU - Kardia, Sharon L.R.

AU - Kasiman, Katherine

AU - Knight, Julia A.

AU - Lahti, Jari

AU - Lawlor, Debbie A.

AU - Magnusson, Patrik K.E.

AU - Margolin, Sara

AU - Marsh, Julie A.

AU - Metspalu, Andres

AU - Olson, Janet E.

AU - Pennell, Craig E.

AU - Polasek, Ozren

AU - Rahman, Iffat

AU - Ridker, Paul M.

AU - Robino, Antonietta

AU - Rudan, Igor

AU - Rudolph, Anja

AU - Salumets, Andres

AU - Schmidt, Marjanka K.

AU - Schoemaker, Minouk J.

AU - Smith, Erin N.

AU - Smith, Jennifer A.

AU - Southey, Melissa

AU - Stöckl, Doris

AU - Swerdlow, Anthony J.

AU - Thompson, Deborah J.

AU - Truong, Therese

AU - Ulivi, Sheila

AU - Waldenberger, Melanie

AU - Wang, Qin

AU - Wild, Sarah

AU - Wilson, James F.

AU - Wright, Alan F.

AU - Zgaga, Lina

AU - Ong, Ken K.

AU - Murabito, Joanne M.

AU - Karasik, David

AU - Murray, Anna

N1 - Funding Information: J.R.B.P is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). D.A.L. and A.F. work in a centre that receives infrastructure funding from the UK Medical Research Council (G0600705) and A.F. is funded by a UK Medical Research Council Post-doctoral research fellowship (0701594). Further information on funding for individual studies is provided in supplementary information. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

PY - 2014/5

Y1 - 2014/5

N2 - 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 atmenarche andmenopause, but to date theknowngenes 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, wefoundnorobust 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.

AB - 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 atmenarche andmenopause, but to date theknowngenes 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, wefoundnorobust 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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DO - 10.1093/hmg/ddt620

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AN - SCOPUS:84897501936

SN - 0964-6906

VL - 23

SP - 2490

EP - 2497

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

M1 - ddt620

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

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