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Age at menarche and adult body mass index: a Mendelian randomization study

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Title: Age at menarche and adult body mass index: a Mendelian randomization study
Authors: Gill, DPS
Brewer, C
Del Greco M, F
Sivakumaran, P
Bowden, J
Sheehan, N
Minelli, C
Item Type: Journal Article
Abstract: Background Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality. Methods The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium. Results There was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25–0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data. Conclusion MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.
Issue Date: 26-Feb-2018
Date of Acceptance: 22-Jan-2018
URI: http://hdl.handle.net/10044/1/56300
DOI: https://dx.doi.org/10.1038/s41366-018-0048-7
ISSN: 0307-0565
Publisher: Nature Publishing Group
Start Page: 1574
End Page: 1581
Journal / Book Title: International Journal of Obesity
Volume: 42
Copyright Statement: © 2018 Springer Nature Limited. All rights reserved.
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Nutrition & Dietetics
PLEIOTROPIC GENETIC-VARIANTS
INSTRUMENTAL VARIABLES
CAUSAL INFERENCE
ADOLESCENT GIRLS
BIRTH COHORT
RISK-FACTORS
OBESITY
WOMEN
ASSOCIATION
PUBERTY
11 Medical And Health Sciences
13 Education
Publication Status: Published
Online Publication Date: 2018-02-26
Appears in Collections:Infectious Disease Epidemiology
National Heart and Lung Institute
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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