Using Transcriptomic Hidden Variables to Infer Context-Specific Genotype Effects in the Brain

Deciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). Applying this approach to two largest brain eQTL datasets (n = 1,100), we show that LVs and GxE eQTLs in one dataset replicate well in the other dataset. Combining the two samples via meta-analysis, 895 GxE eQTLs are identified. On average, GxE effect explains an additional ∼4% variation in expression of each gene that displays a GxE effect. Ten of these 52 genes are associated with cell-type-specific eQTLs, and the remaining genes are multi-functional. Furthermore, after substituting LVs with expression of transcription factors (TF), we found 91 TF-specific eQTLs, which demonstrates an important use of our brain GxE eQTLs.