Genetic regulatory effects in response to a high cholesterol, high fat diet in baboons

Disease-associated loci discovered through genome-wide association studies (GWAS) are primarily located in non-coding regions with putative regulatory effects on gene expression. Steady-state, standard expression quantitative trait loci (eQTLs) explain only a limited portion of GWAS signals, while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Here, we characterized gene-by-diet effects in a baboon model system. By analyzing three tissue types obtained from 99 captive baboons, we identify hundreds of diet-responsive eQTLs with high tissue specificity. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs of genes associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the dynamic complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using the baboon model