MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization.
MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization.
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DOI：
10.1038/srep16645
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发表时间：
2015-11-16
影响因子：
4.6
通讯作者：
Davey Smith G
中科院分区：
文献类型：
--
作者：
Millard LA;Davies NM;Timpson NJ;Tilling K;Flach PA;Davey Smith G
观察性队列研究可以提供具有各种表型变量的丰富数据集。然而，根据定义，假设驱动的流行病学分析只测试研究人员选择的特定假设。此外，观察性分析可能无法提供可靠的因果关系证据，因为它们容易受到混淆、反向因果关系和测量误差的影响。以体重指数（BMI）为例，我们展示了一种新的扩展全表型关联研究（pheWAS）方法，使用基因型仪器自动筛选，以筛选任何数量的表型结果之间的因果关系。我们使用了来自ALSPAC数据集的8，121名儿童的样本，并测试了BMI相关等位基因评分与172种表型结果的线性相关性（样本量可变）。我们还进行了工具变量分析，以估计BMI对每个表型的因果影响。我们发现172个结果中有21个与等位基因得分相关，未调整p < 0.05阈值，并使用Bonferroni校正，排列检验和错误发现率的估计来考虑结果的强度，给出了执行的测试数量。最密切相关的结果包括瘦素、血脂和血压。我们还发现了BMI对全球自我价值感评分影响的新证据。
Observational cohort studies can provide rich datasets with a diverse range of phenotypic variables. However, hypothesis-driven epidemiological analyses by definition only test particular hypotheses chosen by researchers. Furthermore, observational analyses may not provide robust evidence of causality, as they are susceptible to confounding, reverse causation and measurement error. Using body mass index (BMI) as an exemplar, we demonstrate a novel extension to the phenome-wide association study (pheWAS) approach, using automated screening with genotypic instruments to screen for causal associations amongst any number of phenotypic outcomes. We used a sample of 8,121 children from the ALSPAC dataset, and tested the linear association of a BMI-associated allele score with 172 phenotypic outcomes (with variable sample sizes). We also performed an instrumental variable analysis to estimate the causal effect of BMI on each phenotype. We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed. The most strongly associated outcomes included leptin, lipid profile, and blood pressure. We also found novel evidence of effects of BMI on a global self-worth score.