Discovery and Replication of Pathway-Based Trans-Expression Quantitative Trait Loci

Abstract

A logical mechanism by which SNPs affect the pathophysiology of disease is through altering the expression of genes. Several studies have explored how SNPs alter expression of nearby genes (cis-eQTLs), but far fewer studies have explored distant effects (trans-eQTLs). This is likely due to the dramatic expansion of statistical tests required and the limited interpretability of results. We hypothesize that distant effects seen in trans-eQTLs are propagated or mediated by biological pathways. To investigate this hypothesis, we performed a focused trans-eQTL analysis on SNPs with known cis-effects by applying Signaling Pathway Impact Analysis (SPIA) to two independent datasets that have both genotype and gene-expression data. Fifteen SNP-Pathway associations were identified and replicated after correction for multiple testing. Given our requirement that all SNPs have cis-effects we performed conditional analyses to determine the effect of the cis-gene expression on our SNP-Pathway associations. Additionally, we annotated these results for functional elements from the ENCODE project to determine biological plausibility and generalizability. In summary, we identify trans-eQTL effects within the context of biological pathways that replicate across multiple ethnic populations.