论文标题
考虑使用相关仪器变体的两样本孟德尔随机化中相关的水平多效性
Accounting for correlated horizontal pleiotropy in two-sample Mendelian randomization using correlated instrumental variants
论文作者
论文摘要
孟德尔随机化(MR)是一种有力的方法,可以检查健康风险因素与观察性研究结果之间的因果关系。由于全基因组关联研究(GWASS)的扩散和充分访问的GWASS摘要统计数据,已经开发了多种摘要数据的两种两样本MR方法来检测或说明水平多效性,主要基于以下假设,即变体对暴露(γ)和水平pleiotroppy的效果是独立的。该假设太严格了,由于相关的水平多效性(CHP),因此很容易违反。为了解释此CHP,我们提出了一种贝叶斯方法MR-CORR2,该方法使用正交投影将γ和α的双变量正态分布重新分配,并在减轻CHP的影响之前进行Spike-SLAB。我们开发了一种具有并行吉布斯采样的有效算法。为了证明MR-CORR2比现有方法的优势,我们进行了全面的仿真研究,以比较I型误差控制和各种情况下的点估计值。通过应用MR-CORR2在两组复杂性状中研究对之间的关系,我们没有确定HDL-C和CAD之间的矛盾因果关系。此外,结果为复杂性状之间的因果网络提供了新的观点。开发的R软件包和代码以复制所有结果,请访问https://github.com/qingcheng0218/mr.corr2。
Mendelian randomization (MR) is a powerful approach to examine the causal relationships between health risk factors and outcomes from observational studies. Due to the proliferation of genome-wide association studies (GWASs) and abundant fully accessible GWASs summary statistics, a variety of two-sample MR methods for summary data have been developed to either detect or account for horizontal pleiotropy, primarily based on the assumption that the effects of variants on exposure (γ) and horizontal pleiotropy (α) are independent. This assumption is too strict and can be easily violated because of the correlated horizontal pleiotropy (CHP). To account for this CHP, we propose a Bayesian approach, MR-Corr2, that uses the orthogonal projection to reparameterize the bivariate normal distribution for γ and α, and a spike-slab prior to mitigate the impact of CHP. We develop an efficient algorithm with paralleled Gibbs sampling. To demonstrate the advantages of MR-Corr2 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-Corr2 to study the relationships between pairs in two sets of 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. The developed R package and code to reproduce all the results are available at https://github.com/QingCheng0218/MR.Corr2.