From the Department of Neurology and Neurosurgery (A.H.), Department of Human Genetics (J.A.M., V.F., J.B.R.), Department of Medicine (J.B.R.), and Department of Epidemiology, Biostatistics and Occupational Health (J.B.R.), McGill University; Centre for Clinical Epidemiology (A.H., J.A.M., V.F., J.B.R.), Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; MRC Integrative Epidemiology Unit (R.M., G.D.S.), School of Social and Community Medicine, and Population Health Sciences (R.M., G.D.S., S.J.S.), Bristol Medical School, University of Bristol; Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge; and Department of Twin Research and Genetic Epidemiology (J.B.R.), King's College London, UK.
Neurology. 2019 Apr 16;92(16):e1803-e1810. doi: 10.1212/WNL.0000000000007325. Epub 2019 Mar 20.
To investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.
We used 372 genetic variants strongly associated with age at menarche in a genome-wide association study (GWAS) involving 329,245 women. The genetic architecture of pubertal timing across both sexes is highly correlated (genetic correlation [ ] = 0.75, = 1.2 × 10), allowing these variants to provide reliable insight into pubertal timing in males as well. The effect of pubertal timing on risk of MS was measured with summary statistics from a GWAS of 14,802 cases with MS and 26,703 controls from the International Multiple Sclerosis Genetics Consortium. Multivariable MR controlling for effects of body mass index (BMI) using genetic data from additional consortia investigated whether pubertal effects on MS were dependent on weight status.
A 1-year increase in genetically predicted age at puberty decreased odds of MS by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86-0.99, = 0.03). However, multivariable MR analysis showed that after accounting for effects on adult BMI, the association of age at puberty with MS susceptibility attenuated (OR 0.96, 95% CI 0.88-1.04, = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.
We found support for an association between higher age at puberty and decreased risk of MS with a magnitude comparable to that reported in observational studies. This effect appears to be largely mediated by the strong association between age at puberty and obesity. A large causal effect of pubertal timing independent of BMI is unlikely.
采用孟德尔随机化（MR）方法研究青春期年龄对多发性硬化症（MS）易感性的潜在因果效应。
我们使用全基因组关联研究（GWAS）中与 329245 名女性的初潮年龄强烈相关的 372 个遗传变异。两性青春期时间的遗传结构高度相关（遗传相关性[ ]=0.75， =1.2×10），因此这些变异也可以可靠地反映男性的青春期时间。使用国际多发性硬化症遗传学联合会（International Multiple Sclerosis Genetics Consortium）的 MS 病例 14802 例和对照 26703 例的 GWAS 汇总统计数据来衡量青春期时间对 MS 风险的影响。使用来自其他联合会的遗传数据进行多变量 MR，控制体重指数（BMI）的影响，以研究青春期对 MS 的影响是否取决于体重状况。
遗传预测的青春期年龄每增加 1 年，MS 的几率降低 8%（比值比[OR]0.92，95%置信区间[CI]0.86-0.99， =0.03）。然而，多变量 MR 分析表明，在考虑到对成人 BMI 的影响后，青春期年龄与 MS 易感性的关联减弱（OR 0.96，95%CI0.88-1.04， =0.36）。当纳入儿童 BMI 时，得到了类似的结果。敏感性分析没有提供遗传多效性的主要偏差证据。
我们发现青春期年龄较高与 MS 风险降低之间存在关联，其幅度与观察性研究报告的相似。这种效应似乎主要是由青春期年龄与肥胖之间的强烈关联所介导的。青春期时间与 BMI 无关的因果效应较大是不太可能的。
