Mumby Hannah S, Elks Cathy E, Li Shengxu, Sharp Stephen J, Khaw Kay-Tee, Luben Robert N, Wareham Nicholas J, Loos Ruth J F, Ong Ken K
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, P.O. Box 285, Cambridge CB2 0QQ, UK.
J Obes. 2011;2011:180729. doi: 10.1155/2011/180729. Epub 2011 May 18.
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 1 kg/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.
为了推断儿童期体重指数（BMI）与初潮年龄之间的因果关系，我们进行了一项孟德尔随机化分析，使用12个已确定的“增加BMI”的基因变异作为较高BMI的工具变量（IV）。在来自EPIC-诺福克队列的8156名欧洲血统女性中，在39至77岁时测量身高；初潮年龄通过自我回忆获得，20岁时的体重也是如此，并计算20岁时的BMI作为儿童期BMI的替代指标。对12个与BMI相关的常见变异（在FTO、MC4R、TMEM18、GNPDA2、KCTD15、NEGR1、BDNF、ETV5、MTCH2、SEC16B、FAIM2和SH2B1基因内或附近）进行基因分型，并为每个个体计算一个“增加BMI等位基因评分”，方法是将所有12个位点上增加BMI的等位基因数量相加。将这个增加BMI等位基因评分作为BMI的工具变量，预计儿童期BMI每增加1kg/m²，初潮提前（12岁之前）的绝对风险将增加6.5%（95%置信区间：4.6 - 8.5%）。虽然孟德尔随机化分析依赖于一些假设，但我们的研究结果支持BMI对初潮提前有因果效应，并表明儿童肥胖患病率的上升将导致初潮提前患病率出现类似趋势。
