Hindawi Publishing Corporation Journal of Obesity Volume 2011, Article ID 180729, 6 pages doi:10.1155/2011/180729 Research Article Mendelian Randomisation Study of Childhood BMI and Early Menarche Hannah S. Mumby, 1 Cathy E. Elks, 1 Shengxu Li, 1 Stephen J. Sharp, 1 Kay-Tee Khaw, 2 Robert N. Luben, 2 Nicholas J. Wareham, 1 Ruth J. F. Loos, 1 and Ken K. Ong 1 1 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, P.O. Box 285, Cambridge CB2 0QQ, UK 2 Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0SR, UK Correspondence should be addressed to Ken K. Ong, ken.ong@mrc-epid.cam.ac.uk Received 1 December 2010; Revised 4 April 2011; Accepted 7 April 2011 Academic Editor: Angelo Pietrobelli Copyright © 2011 Hannah S. Mumby et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To infer the causal association between childhood BMI and age at menarche, we performed a mendelian randomisation analysis using twelve established “BMI-increasing” genetic variants as an instrumental variable (IV) for higher BMI. In 8,156 women of European descent from the EPIC-Norfolk cohort, height was measured at age 39–77 years; age at menarche was self-recalled, as was body weight at age 20 years, and BMI at 20 was calculated as a proxy for childhood BMI. DNA was genotyped for twelve BMI- associated common variants (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, MTCH2, SEC16B, FAIM2 and SH2B1), and for each individual a “BMI-increasing-allele-score” was calculated by summing the number of BMI-increasing alleles across all 12 loci. Using this BMI-increasing-allele-score as an instrumental variable for BMI, each 1kg/m 2 increase in childhood BMI was predicted to result in a 6.5% (95% CI: 4.6–8.5%) higher absolute risk of early menarche (before age 12 years). While mendelian randomisation analysis is dependent on a number of assumptions, our findings support a causal effect of BMI on early menarche and suggests that increasing prevalence of childhood obesity will lead to similar trends in the prevalence of early menarche. 1. Introduction Early age at menarche, the onset of menstrual periods in girls, is associated with increased risks of adverse health outcomes such as breast, ovarian, and endometrial cancer, hypertension, type 2 diabetes, and cardiovascular disease [1, 2]. Earlier age at menarche is also associated with increased risk for a number of psychosocial outcomes in adolescence including depression, eating disorders, substance abuse, sexual risk-taking and teenage pregnancy [3]. It has been suggested that childhood BMI has a causal effect on the risk for early menarche and there are a number of strongly plausible biological mechanisms [4, 5]. However, discordant secular trends in obesity and age at menarche have raised doubts about the causal nature of these associations. In developed countries, a long-term trend towards earlier menarche has been observed from the late 1800s to the mid 1900s [6]. In many countries these trends appear to have slowed or even stopped since around 1950 [6] while the prevalence of childhood overweight and obesity has increased since the 1980s [7]. It is possible, therefore, that the apparent association between higher BMI and earlier age at menarche might be confounded by other factors such as diet or exposure to endocrine disruptors [8]. The association could also be explained by reverse causality as the progression of puberty in girls is accompanied by rapid gains in body weight and body fat [9]. Mendelian randomisation, using robust genetic vari- ants as “instrumental variables” [10], has been suggested as an approach to avoid the problems of confounding, residual confounding and specificity that are experienced by traditional epidemiological studies [11]. For example, Mendelian randomisation studies have demonstrated the causal effects of low-density lipoprotein (LDL) cholesterol on risk of myocardial infarction [12], apparent protective effects of high-density lipoprotein (HDL) cholesterol on