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Age at menarche and lung function: a Mendelian randomization study

Gill, Dipender; Sheehan, Nuala A.; Wielscher, Matthias; Shrine, Nick; Amaral, Andre F. S.; Thompson, John R.; Granell, Raquel; Leynaert, Bénédicte; Real, Francisco Gómez; Hall, Ian P.; Tobin, Martin D.; Auvinen, Juha; Ring, Susan M.; Jarvelin, Marjo-Riitta; Wain, Louise V.; Henderson, John; Jarvis, Deborah; Minelli, Cosetta


Dipender Gill

Nuala A. Sheehan

Matthias Wielscher

Nick Shrine

Andre F. S. Amaral

John R. Thompson

Raquel Granell

Bénédicte Leynaert

Francisco Gómez Real

Professor of Molecular Medicine

Martin D. Tobin

Juha Auvinen

Susan M. Ring

Marjo-Riitta Jarvelin

Louise V. Wain

John Henderson

Deborah Jarvis

Cosetta Minelli


A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8–47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2–69.9; p = 0.001). In adolescent girls we found an opposite effect (−56.5 mL; −108.3 to −4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).


Gill, D., Sheehan, N. A., Wielscher, M., Shrine, N., Amaral, A. F. S., Thompson, J. R., …Minelli, C. (2017). Age at menarche and lung function: a Mendelian randomization study. European Journal of Epidemiology, 32(8), 701-710.

Journal Article Type Article
Acceptance Date Jun 7, 2017
Online Publication Date Jun 17, 2017
Publication Date 2017-08
Deposit Date Jul 20, 2017
Publicly Available Date Jul 20, 2017
Journal European Journal of Epidemiology
Print ISSN 0393-2990
Electronic ISSN 1573-7284
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 32
Issue 8
Pages 701-710
Keywords Mendelian randomization ; Menarche ; Puberty ; Lung function ; FVC ; FEV1/FVC
Public URL
Publisher URL
Copyright Statement Copyright information regarding this work can be found at the following address:


s10654-017-0272-9.pdf (353 Kb)

Copyright Statement
Copyright information regarding this work can be found at the following address:

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