Associations of genetic variants with gene expression factors reveal biological pathways underlying complex traits

Genome-wide association studies (GWASs) have mapped a large number of variants associated with common traits and diseases. To translate these associations into mechanistic knowledge, it is important to understand the downstream genes and biological processes that mediate the effects of these variants on phenotypes. One strategy to link trait-associated genetic variants with their downstream target genes is trans-expression quantitative trait locus (trans-eQTL) mapping. Nevertheless, due to the small effects of trans-eQTLs and the large multiple testing burden arising from the vast number of SNP-gene combinations, it is challenging to identify trans-eQTLs in practice. In this work, we propose a different strategy, focusing on the genetic effects of variants on "expression factors," which were derived from expression data and serve as proxies for activities of biological pathways. We found that variants associated with common immune traits are frequently associated in trans with the expression factors derived from curated pathways, suggesting that variants with phenotypic effects often perturb the transcriptional networks. Using a newly developed statistical strategy, the effect consistency test, we identified dozens of pathways that may mediate the effects of trait-associated variants on immune phenotypes. Our study thus provided a new framework to link genetic variations to phenotypes.