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.
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.
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.
MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.
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This study has been performed using the UK Biobank Resource, and we thank the participants, field workers, and data managers for their contribution.
Conception of the study: DG and CFB. Design of the study protocol: DG, FDGM, JB, and CM. Analysis of the data: DG, FDGM, and CM. Drafting of the paper: DG, CFB, and PS. Interpretation of the findings and revision of the paper: All authors. DG, FDGM, and CM had access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. DG affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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