Transcripts with high distal heritability mediate genetic effects on complex metabolic traits.

Although many genes are subject to local regulation, recent evidence suggests that complex distal regulation may be more important in mediating phenotypic variability. To assess the role of distal gene regulation in complex traits, we combined multi-tissue transcriptomes with physiological outcomes to model diet-induced obesity and metabolic disease in a population of Diversity Outbred mice. Using a novel high-dimensional mediation analysis, we identified a composite transcriptome signature that summarized genetic effects on gene expression and explained 30% of the variation across all metabolic traits.