MR-Corr2: a two-sample Mendelian randomization method that accounts for correlated horizontal pleiotropy using correlated instrumental variants
MR-Corr2: a two-sample Mendelian randomization method that accounts for correlated horizontal pleiotropy using correlated instrumental variants
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DOI：
10.1093/bioinformatics/btab646
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发表时间：
2021-09-09
期刊：
影响因子：
5.8
通讯作者：
Liu, Jin
中科院分区：
文献类型：
--
作者：
Cheng, Qing;Qiu, Tingting;Liu, Jin
动机：孟德尔随机化（MR）是检验健康风险因素与观察性研究结果之间因果关系的一种有价值的工具。随着全基因组关联研究的增多，人们开发了各种用于汇总数据的双样本MR方法来解释水平多效性（HP），主要基于变异对暴露（γ）和HP （α）的影响是独立的假设。在实践中，这个假设过于严格，由于相关的HP很容易被违反。结果：为了解释这种相关的HP，我们提出了一种贝叶斯方法，MR-Corr(2)，它使用正交投影来重新参数化gamma和alpha的二元正态分布，并在减轻相关HP的影响之前使用尖峰板。我们还开发了一种高效的并行吉布斯采样算法。为了证明MR-Corr(2)相对于现有方法的优势，我们进行了全面的仿真研究，比较了不同场景下i型误差控制和点估计的效果。通过应用MR-Corr(2)来研究复杂性状中暴露-结果对之间的关系，我们没有发现HDL-c和CAD之间矛盾的因果关系。此外，研究结果还为研究复杂性状之间的因果网络提供了新的视角。
Motivation: Mendelian randomization (MR) is a valuable tool to examine the causal relationships between health risk factors and outcomes from observational studies. Along with the proliferation of genome-wide association studies, a variety of two-sample MR methods for summary data have been developed to account for horizontal pleiotropy (HP), primarily based on the assumption that the effects of variants on exposure (gamma) and HP (alpha) are independent. In practice, this assumption is too strict and can be easily violated because of the correlated HP.Results: To account for this correlated HP, we propose a Bayesian approach, MR-Corr(2), that uses the orthogonal projection to reparameterize the bivariate normal distribution for gamma and alpha, and a spike-slab prior to mitigate the impact of correlated HP. We have also developed an efficient algorithm with paralleled Gibbs sampling. To demonstrate the advantages of MR-Corr(2) over existing methods, we conducted comprehensive simulation studies to compare for both type-I error control and point estimates in various scenarios. By applying MR-Corr(2) to study the relationships between exposure-outcome pairs in complex traits, we did not identify the contradictory causal relationship between HDL-c and CAD. Moreover, the results provide a new perspective of the causal network among complex traits.