A mediation analysis of schizophrenia variants: Risk alleles may affect a gene’s expression differently from how the expression affects risk

Variants identified by Genome wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Additionally eQTL analyses show that variants often affect more than one gene. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander. It also puts into question the direction of the effect of a gene’s expression on the risk, since the many genes regulated by the same variant may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for a mediation analysis of schizophrenia-associated variants. We find that indeed eQTL targets often mediate risk but the direction in which expression affects risk is often different from the direction in which the risk allele changes expression. Of 38 genes significant for mediation in both datasets 33 showed consistent direction (Chi test P=6*10) and for 15 of them (45%) the expression change associated with the risk allele was protective, which suggests the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease and those that are might have different than expected directions.