A genome-wide association study of early menopause and the combined impact of identified variants

John R B Perry; Tanguy Corre; Tõnu Esko; Daniel I Chasman; Krista Fischer; Nora Franceschini; Chunyan He; Zoltan Kutalik; Massimo Mangino; Lynda M Rose; Albert Vernon Smith; Lisette Stolk; Patrick Sulem; Michael N Weedon; Wei V Zhuang; Alice Arnold; Alan Ashworth; Sven Bergmann; Julie E Buring; Andrea Burri; Constance Chen; Marilyn C Cornelis; David J Couper; Mark O Goodarzi; Vilmundur Gudnason; Tamara Harris; Albert Hofman; Michael Jones; Peter Kraft; Lenore Launer; Joop S E Laven; Guo Li; Barbara McKnight; Corrado Masciullo; Lili Milani; Nicholas Orr; Bruce M Psaty; Paul M Ridker; Fernando Rivadeneira; Cinzia Sala; Andres Salumets; Minouk Schoemaker; Michela Traglia; Gérard Waeber; Stephen J Chanock; Ellen W Demerath; Melissa Garcia; Susan E Hankinson; Frank B Hu; David J Hunter; ReproGen Consortium

doi:10.1093/hmg/dds551

A genome-wide association study of early menopause and the combined impact of identified variants

John R B Perry, Tanguy Corre, Tõnu Esko, Daniel I Chasman, Krista Fischer, Nora Franceschini, Chunyan He, Zoltan Kutalik, Massimo Mangino, Lynda M Rose, Albert Vernon Smith, Lisette Stolk, Patrick Sulem, Michael N Weedon, Wei V Zhuang, Alice Arnold, Alan Ashworth, Sven Bergmann, Julie E Buring, Andrea BurriConstance Chen, Marilyn C Cornelis, David J Couper, Mark O Goodarzi, Vilmundur Gudnason, Tamara Harris, Albert Hofman, Michael Jones, Peter Kraft, Lenore Launer, Joop S E Laven, Guo Li, Barbara McKnight, Corrado Masciullo, Lili Milani, Nicholas Orr, Bruce M Psaty, Paul M Ridker, Fernando Rivadeneira, Cinzia Sala, Andres Salumets, Minouk Schoemaker, Michela Traglia, Gérard Waeber, Stephen J Chanock, Ellen W Demerath, Melissa Garcia, Susan E Hankinson, Frank B Hu, David J Hunter, ReproGen Consortium

School of Medicine, Dentistry and Biomedical Sciences

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

103 Citations (Scopus)

Abstract

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Original language	English
Pages (from-to)	1465-72
Number of pages	8
Journal	Human Molecular Genetics
Volume	22
Issue number	7
DOIs	https://doi.org/10.1093/hmg/dds551
Publication status	Published - 01 Apr 2013

Keywords

Case-Control Studies
Female
Gene Frequency
Genome-Wide Association Study
Humans
Menopause, Premature
Polymorphism, Single Nucleotide
Primary Ovarian Insufficiency
Quantitative Trait Loci
Risk
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

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Perry, J. R. B., Corre, T., Esko, T., Chasman, D. I., Fischer, K., Franceschini, N., He, C., Kutalik, Z., Mangino, M., Rose, L. M., Vernon Smith, A., Stolk, L., Sulem, P., Weedon, M. N., Zhuang, W. V., Arnold, A., Ashworth, A., Bergmann, S., Buring, J. E., ... ReproGen Consortium (2013). A genome-wide association study of early menopause and the combined impact of identified variants. Human Molecular Genetics, 22(7), 1465-72. https://doi.org/10.1093/hmg/dds551

@article{03e46e0088094a528af66513762257c3,

title = "A genome-wide association study of early menopause and the combined impact of identified variants",

abstract = "Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.",

keywords = "Case-Control Studies, Female, Gene Frequency, Genome-Wide Association Study, Humans, Menopause, Premature, Polymorphism, Single Nucleotide, Primary Ovarian Insufficiency, Quantitative Trait Loci, Risk, Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't",

author = "Perry, {John R B} and Tanguy Corre and T{\~o}nu Esko and Chasman, {Daniel I} and Krista Fischer and Nora Franceschini and Chunyan He and Zoltan Kutalik and Massimo Mangino and Rose, {Lynda M} and {Vernon Smith}, Albert and Lisette Stolk and Patrick Sulem and Weedon, {Michael N} and Zhuang, {Wei V} and Alice Arnold and Alan Ashworth and Sven Bergmann and Buring, {Julie E} and Andrea Burri and Constance Chen and Cornelis, {Marilyn C} and Couper, {David J} and Goodarzi, {Mark O} and Vilmundur Gudnason and Tamara Harris and Albert Hofman and Michael Jones and Peter Kraft and Lenore Launer and Laven, {Joop S E} and Guo Li and Barbara McKnight and Corrado Masciullo and Lili Milani and Nicholas Orr and Psaty, {Bruce M} and Ridker, {Paul M} and Fernando Rivadeneira and Cinzia Sala and Andres Salumets and Minouk Schoemaker and Michela Traglia and G{\'e}rard Waeber and Chanock, {Stephen J} and Demerath, {Ellen W} and Melissa Garcia and Hankinson, {Susan E} and Hu, {Frank B} and Hunter, {David J} and {ReproGen Consortium}",

year = "2013",

month = apr,

day = "1",

doi = "10.1093/hmg/dds551",

language = "English",

volume = "22",

pages = "1465--72",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "7",

}

Perry, JRB, Corre, T, Esko, T, Chasman, DI, Fischer, K, Franceschini, N, He, C, Kutalik, Z, Mangino, M, Rose, LM, Vernon Smith, A, Stolk, L, Sulem, P, Weedon, MN, Zhuang, WV, Arnold, A, Ashworth, A, Bergmann, S, Buring, JE, Burri, A, Chen, C, Cornelis, MC, Couper, DJ, Goodarzi, MO, Gudnason, V, Harris, T, Hofman, A, Jones, M, Kraft, P, Launer, L, Laven, JSE, Li, G, McKnight, B, Masciullo, C, Milani, L, Orr, N, Psaty, BM, Ridker, PM, Rivadeneira, F, Sala, C, Salumets, A, Schoemaker, M, Traglia, M, Waeber, G, Chanock, SJ, Demerath, EW, Garcia, M, Hankinson, SE, Hu, FB, Hunter, DJ & ReproGen Consortium 2013, 'A genome-wide association study of early menopause and the combined impact of identified variants', Human Molecular Genetics, vol. 22, no. 7, pp. 1465-72. https://doi.org/10.1093/hmg/dds551

TY - JOUR

T1 - A genome-wide association study of early menopause and the combined impact of identified variants

AU - Perry, John R B

AU - Corre, Tanguy

AU - Esko, Tõnu

AU - Chasman, Daniel I

AU - Fischer, Krista

AU - Franceschini, Nora

AU - He, Chunyan

AU - Kutalik, Zoltan

AU - Mangino, Massimo

AU - Rose, Lynda M

AU - Vernon Smith, Albert

AU - Stolk, Lisette

AU - Sulem, Patrick

AU - Weedon, Michael N

AU - Zhuang, Wei V

AU - Arnold, Alice

AU - Ashworth, Alan

AU - Bergmann, Sven

AU - Buring, Julie E

AU - Burri, Andrea

AU - Chen, Constance

AU - Cornelis, Marilyn C

AU - Couper, David J

AU - Goodarzi, Mark O

AU - Gudnason, Vilmundur

AU - Harris, Tamara

AU - Hofman, Albert

AU - Jones, Michael

AU - Kraft, Peter

AU - Launer, Lenore

AU - Laven, Joop S E

AU - Li, Guo

AU - McKnight, Barbara

AU - Masciullo, Corrado

AU - Milani, Lili

AU - Orr, Nicholas

AU - Psaty, Bruce M

AU - Ridker, Paul M

AU - Rivadeneira, Fernando

AU - Sala, Cinzia

AU - Salumets, Andres

AU - Schoemaker, Minouk

AU - Traglia, Michela

AU - Waeber, Gérard

AU - Chanock, Stephen J

AU - Demerath, Ellen W

AU - Garcia, Melissa

AU - Hankinson, Susan E

AU - Hu, Frank B

AU - Hunter, David J

AU - ReproGen Consortium

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

AB - Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

KW - Case-Control Studies

KW - Female

KW - Gene Frequency

KW - Genome-Wide Association Study

KW - Humans

KW - Menopause, Premature

KW - Polymorphism, Single Nucleotide

KW - Primary Ovarian Insufficiency

KW - Quantitative Trait Loci

KW - Risk

KW - Journal Article

KW - Meta-Analysis

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/hmg/dds551

DO - 10.1093/hmg/dds551

M3 - Article

C2 - 23307926

SN - 0964-6906

VL - 22

SP - 1465

EP - 1472

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 7

ER -

A genome-wide association study of early menopause and the combined impact of identified variants

Abstract

Keywords

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