Identification of Trans-eQTLs Using Mediation Analysis with Multiple Mediators

摘要

Mapping expression quantitative trait loci (eQTLs) has provided insight into gene regulation. Compared to cis-eQTLs, the regulatory mechanisms of trans-eQTLs are less known. Previous studies suggest that trans-eQTLs may regulate expression of remote genes by altering the expression of nearby genes. Trans-association has been studied in the mediation analysis with a single mediator. However, prior applications with one mediator are prone to model misspecification due to correlations between genes. Motivated from the observation that trans-eQTLs are more likely to associate with more than one cis-gene than randomly selected SNPs in the GTEx dataset, we developed a computational method to identify trans-eQTLs that are mediated by multiple mediators. We proposed two hypothesis tests for testing the total mediation effect (TME) and the component-wise mediation effects (CME). We demonstrated in simulation studies that the type I error rates were controlled in both tests despite model misspecification. Multiple mediator analysis had increased power to detect mediated trans-eQTLs, especially in large samples. In the HapMap3 data, we identified 11 more mediated trans-eQTLs in the African populations. Moreover, the mediated trans-eQTLs in the HapMap3 samples are more likely to be trait-associated SNPs. This study demonstrated that trans-eQTLs are more likely to associate with multiple cis-genes than randomly selected SNPs. Mediation analysis with multiple mediators improves power of identification of mediated trans-eQTLs, especially in large samples.