Critical reasoning on the co-expression module QTL in the dorsolateral prefrontal cortex

Abstract

Expression quantitative trait locus (eQTL) analysis is a popular method of gaining insight into the function of regulatory variation. While cis-eQTL resources have been instrumental in linking GWAS variants to gene function, complex trait heritability may be additionally mediated by other forms of gene regulation. Towards this end, novel eQTL methods leverage gene co-expression (module-QTL) to investigate joint regulation of gene modules by single genetic variants. Here we broadly define a "module-QTL" as the association of a genetic variant with a summary measure of gene co-expression. This approach aims to reduce the multiple testing burden of a trans-eQTL search through the consolidation of gene-based testing, and provide biological context to eQTLs shared between genes. In this article we provide an in-depth examination of the co-expression module eQTL (module-QTL) through literature review, theoretical investigation, and real-data application of the module-QTL to three large prefrontal cortex genotype-RNA seq datasets. We find module-QTLs in our study that are disease-associated and reproducible are not additionally informative beyond cis- or trans-eQTLs for module genes. Through comparison to prior studies, we highlight promises and limitations of the module-QTL across study designs, and provide recommendations for further investigation of the module-QTL framework.