Types of Cis- and Trans-Gene Regulation of Expression Quantitative Trait Loci Across Human Tissues

Abstract

AbstractExpression quantitative trait loci (eQTLs) have been identified for most genes in the human genome across nearly 50 tissues or cell types. While most of the eQTLs are near the associated genes, some can be far away or on different chromosomes, with the regulatory mechanisms largely unknown. Here, we study cis- and trans-regulation of eQTLs across multiple tissues and cell types. Specifically, we constructed trios consisting of an eQTL, its cis-gene and trans-gene and inferred the regulatory relationships with causal network inference. We identify multiple types of regulatory networks for trios: across all the tissues, more than half of the trios are inferred to be conditionally independent, where the two genes are conditionally independent given the genotype of the eQTL (cis-gene ← eQTL → trans-gene). Around 1.5% of the trios are inferred to be mediation (eQTL → mediator → target), around 1.3% fully connected among the three nodes, and just a handful v-structures (eQTL → gene 1 ← gene 2). Unexpectedly, across the tissues, on average more than half of the mediation trios have the trans-gene as the mediator. Most of the mediators (cis and trans) are tissue specific. Furthermore, cis-gene mediators are significantly enriched for protein-coding genes compared with the genome average, whereas trans-gene mediators are significantly enriched for pseudogenes and depleted for long noncoding RNAs (lncRNAs).