Effect of age at puberty on risk of multiple sclerosis A mendelian randomization study
Effect of age at puberty on risk of multiple sclerosis A mendelian randomization study
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DOI：
10.1212/wnl.0000000000007325
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发表时间：
2019-04-16
期刊：
影响因子：
9.9
通讯作者：
Richards, J. Brent
中科院分区：
文献类型：
--
作者：
Harroud, Adil;Morris, John A.;Richards, J. Brent
目的使用孟德尔随机化（MR）方法研究青春期年龄对多发性硬化症（MS）易感性的潜在因果影响。方法我们在一项涉及329，245名女性的全基因组关联研究（GWAS）中使用了372种与初潮年龄密切相关的遗传变异。两性青春期时间的遗传结构高度相关（遗传相关性[r（g）] = 0.75，p = 1.2 x 10（-79）），这使得这些变异也可以提供对男性青春期时间的可靠了解。青春期时间对MS风险的影响通过来自国际多发性硬化遗传学联盟的14，802例MS病例和26，703例对照的GWAS的汇总统计来测量。多变量MR控制的影响，身体质量指数（BMI）的遗传数据，从其他财团调查青春期对MS的影响是否依赖于体重status.ResultsA 1年的增长，在青春期遗传预测的年龄下降了8%（比值比[OR] 0.92，95%置信区间[CI] 0.86-0.99，p = 0.03）MS的赔率。然而，多变量MR分析显示，在考虑对成人BMI的影响后，青春期年龄与MS易感性的相关性减弱（OR 0.96，95%CI 0.88-1.04，p = 0.36）。当儿童BMI被纳入时，也得到了类似的结果。敏感性分析没有提供任何证据表明，从遗传pleiotropy.ConclusionsWe发现支持青春期较高的年龄和MS的风险降低的幅度相媲美的观察性研究报告之间的关联。这种影响似乎在很大程度上是由青春期年龄和肥胖之间的强关联介导的。青春期时间独立于BMI的大的因果效应是不太可能的。
ObjectiveTo investigate the potential for a causal effect of age at puberty on multiple sclerosis (MS) susceptibility using a mendelian randomization (MR) approach.MethodsWe 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 [r(g)] = 0.75, p = 1.2 x 10(-79)), 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.ResultsA 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, p = 0.03). However, multivariableMR 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, p = 0.36). Similar results were obtained when childhood BMI was incorporated. Sensitivity analyses provided no evidence of major bias from genetic pleiotropy.ConclusionsWe 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.