Cross-phenotype meta-analysis reveals large-scale trans-eQTLs mediating patterns of transcriptional co-regulation

TL;DR

This study identifies large-scale trans-eQTLs that influence groups of co-regulated genes, revealing insights into cellular gene regulation networks through a novel multi-gene association approach.

Contribution

It introduces a new method for detecting trans-eQTLs by identifying SNPs associated with multiple genes simultaneously, uncovering regulatory gene networks.

Findings

Identified 732 trans-eQTLs that replicate across populations.

Each trans-eQTL controls large regulons of co-regulated genes.

Mapped gene networks controlled by transcription factors.

Abstract

Genetic variation affecting gene regulation is a central driver of phenotypic differences between individuals and can be used to uncover how biological processes are organized in a cell. Although detecting cis-eQTLs is now routine, trans-eQTLs have proven more challenging to find due to the modest variance explained and the multiple tests burden of testing millions of SNPs for association to thousands of transcripts. Here, we successfully map trans-eQTLs with the complementary approach of looking for SNPs associated to the expression of multiple genes simultaneously. We find 732 trans- eQTLs that replicate across two continental populations; each trans-eQTL controls large groups of target transcripts (regulons), which are part of interacting networks controlled by transcription factors. We are thus able to uncover co-regulated gene sets and begin describing the cell circuitry of gene regulation.