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; kConFab Investigators; Sharon L R Kardia; Katherine Kasiman; Julia A Knight; Jari Lahti; Debbie A Lawlor; Patrik K E Magnusson; Sara Margolin; ReproGen Consortium

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, kConFab Investigators, Sharon L R Kardia, Katherine Kasiman, Julia A Knight, Jari Lahti, Debbie A Lawlor, Patrik K E Magnusson, Sara Margolin, ReproGen Consortium

^*Corresponding author for this work

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

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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.

Original language	English
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
Publication status	Published - 1 May 2014

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DNA mismatch repair gene MSH6 implicated in determining age at natural menopauseFinal published version, 315 KBLicence: CC BY

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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., ... ReproGen Consortium (2014). DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Human Molecular Genetics, 23(9), 2490-2497. https://doi.org/10.1093/hmg/ddt620

@article{381f2d6f7dc3443cbccea392f1c63813,

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 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.",

author = "Perry, {John R B} and Yi-Hsiang Hsu 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 {kConFab Investigators} 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 {ReproGen Consortium} and Lisette Stolk and Visser, {Jenny A.} and Andr{\'e} Uitterlinden and Fernando Rivadeneira and {van Meurs}, Joyce and Bert Hofman and Joop Laven",

year = "2014",

month = may,

day = "1",

doi = "10.1093/hmg/ddt620",

language = "English",

volume = "23",

pages = "2490--2497",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

Perry, JRB, Hsu, Y-H, 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, kConFab Investigators, Kardia, SLR, Kasiman, K, Knight, JA, Lahti, J, Lawlor, DA, Magnusson, PKE, Margolin, S & ReproGen Consortium 2014, 'DNA mismatch repair gene MSH6 implicated in determining age at natural menopause', Human Molecular Genetics, vol. 23, no. 9, 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 - kConFab Investigators

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 - ReproGen Consortium

AU - Stolk, Lisette

AU - Visser, Jenny A.

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - van Meurs, Joyce

AU - Hofman, Bert

AU - Laven, Joop

PY - 2014/5/1

Y1 - 2014/5/1

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 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.

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 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.

U2 - 10.1093/hmg/ddt620

DO - 10.1093/hmg/ddt620

M3 - Article

C2 - 24357391

SN - 0964-6906

VL - 23

SP - 2490

EP - 2497

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

ER -

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

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