The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Genet. 2018 May;50(5):693-698. doi: 10.1038/s41588-018-0099-7. Epub 2018 Apr 23.
Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the 'no horizontal pleiotropy' assumption can cause severe bias in MR. We developed the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that the MR-PRESSO test is best suited when horizontal pleiotropy occurs in <50% of instruments. Next we applied the MR-PRESSO test, along with several other MR tests, to complex traits and diseases and found that horizontal pleiotropy (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from -131% to 201%; (iii) induced false-positive causal relationships in up to 10% of relationships; and (iv) could be corrected in some but not all instances.
当变体对孟德尔随机化（MR）中暴露因素的影响之外的疾病也有影响时，就会发生水平多效性。违反“无水平多效性”假设会导致 MR 中严重的偏差。我们开发了孟德尔随机化多效性残差和异常值（MR-PRESSO）检验，以识别多仪器汇总水平 MR 检验中的水平多效性异常值。我们通过模拟表明，当水平多效性在<50%的仪器中发生时，MR-PRESSO 检验最适用。接下来，我们将 MR-PRESSO 检验与其他几种 MR 检验一起应用于复杂特征和疾病，发现水平多效性（i）在 MR 中超过 48%的显著因果关系中是可检测的；（ii）在 MR 中的因果估计中引入了平均从-131%到 201%的扭曲；（iii）在多达 10%的关系中引起了假阳性的因果关系；（iv）在某些但不是所有情况下可以纠正。
