Abstract
Expression quantitative trait locus (eQTL) studies in human cohorts typically detect at least one regulatory signal per gene and have been proposed as a way to explain mechanisms of genetic liability for other traits, as discovered in genome-wide association studies (GWASs). In particular, eQTL signals may colocalize with GWAS signals, suggesting gene expression as a possible mediator. However, recent studies have noted that colocalization occurs infrequently, even when expression is measured in biologically relevant tissues. Most eQTL studies to date include only hundreds of individuals and are underpowered to discover distal regulatory signals explaining smaller fractions of gene expression variance. Using evidence from recent eQTL studies, we demonstrate that limited statistical power due to sample size skews the detection of eQTL signals identified at various signal strengths. We estimate that a sample size of 500 detects <0.1% to 60% of eQTLs for a range of signal strengths and that a sample size of 2,000 detects 36.8% of eQTLs. We show that eQTL signals only discoverable in larger studies exhibit characteristics more similar to those of GWAS signals, including greater distance to the regulated gene and a higher probability of loss-of-function intolerance in the associated gene. Finally, using results from recent eQTL studies and meta-analyses, we observe a large increase in detected colocalizations with GWAS signals compared to previous studies. These findings caution against overinterpreting the absence of colocalization in underpowered studies and provide guidance for designing future eQTL experiments to improve power and complement perturbation-based approaches in characterizing gene-trait mechanisms.