Department of Clinical Pharmacology and Therapeutics, St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.
Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, London, UK.
Int J Obes (Lond). 2018 Sep;42(9):1574-1581. doi: 10.1038/s41366-018-0048-7. Epub 2018 Feb 26.
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/m (95% CI 0.25-0.51 kg/m). 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.
青春期开始的时间与心理和生理后果有关。虽然观察性研究已经表明初潮年龄与成年人体重指数（BMI）之间存在关联，但混杂因素使得很难推断因果关系。
孟德尔随机化（MR）技术不受传统混杂因素的限制，用于研究初潮年龄对成年 BMI 的因果效应是否存在。MR 使用遗传变异作为工具，假设它们仅通过初潮年龄对 BMI 起作用（无 pleiotropy）。使用两样本 MR 方法，个体工具的 MR 估计值之间的异质性被用作 pleiotropy 的替代指标，如果发现则进行敏感性分析。遗传工具及其与初潮年龄关联的估计值是从对 182,416 名女性进行的全基因组关联荟萃分析中获得的。使用英国生物库中 80,465 名女性的数据来估计对成年 BMI 的遗传影响。使用 GIANT 联盟中 70,692 名女性的数据进一步研究初潮年龄对成年 BMI 的因果效应。
工具之间存在 pleiotropy 的证据。使用英国生物库数据，在去除可能产生 pleiotropy 的与儿童 BMI 相关的工具后，跨工具的固定效应荟萃分析表明，初潮年龄每增加 1 年，成年 BMI 降低 0.38 kg/m（95% CI 0.25-0.51 kg/m）。然而，pleiotropy 的证据仍然存在。MR-Egger 回归并未表明存在方向性偏差，并且在使用随机效应模型、多变量 MR、MR-Egger 回归、加权中位数估计量和加权基于模式的估计量进行敏感性分析时，也得到了与固定效应荟萃分析相似的估计值。使用 GIANT 联盟数据复制了因果效应的方向和显著性。
MR 提供了证据支持初潮年龄较早导致成年 BMI 较高的假设。复杂的激素和心理因素可能是造成这种情况的原因。
