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

Area of Science:

• Genetics
• Systems Biology
• Metabolic Disease Research

Background:

• Phenotypic variability in complex traits is influenced by gene regulation.
• Recent evidence points to distal gene regulation playing a critical role.
• Understanding these complex regulatory mechanisms is key to deciphering disease etiology.

Purpose of the Study:

• To investigate the role of distal gene regulation in mediating complex traits.
• To model diet-induced obesity and metabolic disease using multi-tissue transcriptomes and physiological outcomes.
• To identify genetic effects on gene expression that contribute to metabolic variation.

Main Methods:

• Utilized multi-tissue transcriptomes and physiological data from Diversity Outbred mice.
• Applied a novel high-dimensional mediation analysis to model gene expression and metabolic traits.
• Validated findings in an independent mouse cohort and human studies.

Main Results:

• Identified a composite transcriptome signature explaining 30% of variation in metabolic traits.
• The signature was heritable, biologically interpretable, and predictive of obesity.
• Key transcripts showed complex, distal regulation across the genome.

Conclusions:

• Trait-relevant variation in transcription is predominantly distally regulated.
• Distal gene regulation, though complex, is identifiable, interpretable, and translatable across species.
• This highlights distal regulation as a major contributor to phenotypic variability in metabolic diseases.