Arafat Subhi, Minică Camelia C
Department of Biological Psychology,Vrije Universiteit,Amsterdam,the Netherlands.
Twin Res Hum Genet. 2018 Dec;21(6):485-494. doi: 10.1017/thg.2018.65.
The Barker hypothesis states that low birth weight (BW) is associated with higher risk of adult onset diseases, including mental disorders like schizophrenia, major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD). The main criticism of this hypothesis is that evidence for it comes from observational studies. Specifically, observational evidence does not suffice for inferring causality, because the associations might reflect the effects of confounders. Mendelian randomization (MR) - a novel method that tests causality on the basis of genetic data - creates the unprecedented opportunity to probe the causality in the association between BW and mental disorders in observation studies. We used MR and summary statistics from recent large genome-wide association studies to test whether the association between BW and MDD, schizophrenia and ADHD is causal. We employed the inverse variance weighted (IVW) method in conjunction with several other approaches that are robust to possible assumption violations. MR-Egger was used to rule out horizontal pleiotropy. IVW showed that the association between BW and MDD, schizophrenia and ADHD is not causal (all p > .05). The results of all the other MR methods were similar and highly consistent. MR-Egger provided no evidence for pleiotropic effects biasing the estimates of the effects of BW on MDD (intercept = -0.004, SE = 0.005, p = .372), schizophrenia (intercept = 0.003, SE = 0.01, p = .769), or ADHD (intercept = 0.009, SE = 0.01, p = .357). Based on the current evidence, we refute the Barker hypothesis concerning the fetal origins of adult mental disorders. The discrepancy between our results and the results from observational studies may be explained by the effects of confounders in the observational studies, or by the existence of a small causal effect not detected in our study due to weak instruments. Our power analyses suggested that the upper bound for a potential causal effect of BW on mental disorders would likely not exceed an odds ratio of 1.2.
巴克假说指出，低出生体重与成年后发病风险较高有关，这些疾病包括精神分裂症、重度抑郁症（MDD）和注意力缺陷多动障碍（ADHD）等精神障碍。对这一假说的主要批评是，其证据来自观察性研究。具体而言，观察性证据不足以推断因果关系，因为这些关联可能反映了混杂因素的影响。孟德尔随机化（MR）——一种基于基因数据检验因果关系的新方法——为在观察性研究中探究出生体重与精神障碍之间关联的因果关系创造了前所未有的机会。我们使用MR和近期大型全基因组关联研究的汇总统计数据来检验出生体重与MDD、精神分裂症和ADHD之间的关联是否具有因果关系。我们采用逆方差加权（IVW）方法以及其他几种对可能的假设违背具有稳健性的方法。MR-Egger用于排除水平多效性。IVW表明，出生体重与MDD、精神分裂症和ADHD之间的关联不具有因果关系（所有p>.05）。所有其他MR方法的结果相似且高度一致。MR-Egger没有提供证据表明多效性效应会使出生体重对MDD（截距=-0.004，标准误=0.005，p=.372）、精神分裂症（截距=0.003，标准误=0.01，p=.769）或ADHD（截距=0.009，标准误=0.01，p=.357）影响的估计产生偏差。基于当前证据，我们反驳了关于成人精神障碍胎儿起源的巴克假说。我们的结果与观察性研究结果之间的差异可能是由于观察性研究中混杂因素的影响，或者是由于工具变量较弱导致我们的研究未检测到的小因果效应的存在。我们的功效分析表明，出生体重对精神障碍潜在因果效应的上限可能不会超过1.2的优势比。
