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

Area of Science:

• Genetics and Genomics
• Systems Biology
• Metabolic Disease Research

Background:

• Phenotypic variability is influenced by gene regulation, with complex distal regulatory mechanisms gaining recent attention.
• Understanding the role of distal gene regulation is crucial for deciphering complex traits and associated diseases.

Purpose of the Study:

• To investigate the impact of distal gene regulation on complex traits, specifically diet-induced obesity and metabolic disease.
• To develop and validate a method for identifying and interpreting gene expression signatures related to metabolic variation.

Main Methods:

• Combined multi-tissue transcriptomes with physiological outcomes in Diversity Outbred mice.
• Employed novel high-dimensional mediation analysis to identify a composite transcriptome signature.
• Validated the signature in an independent mouse cohort and human studies.

Main Results:

• Identified a heritable composite transcriptome signature explaining 30% of metabolic trait variation.
• The signature is biologically interpretable and predicts obesity status across species.
• Key transcripts in the signature exhibit complex, distal regulatory patterns across the genome.

Conclusions:

• Trait-relevant variation in transcription is predominantly controlled by complex, distal regulatory elements.
• This distal regulation, while complex, is identifiable, interpretable, and potentially translatable across species.
• The findings highlight the importance of distal regulatory networks in shaping complex phenotypes and diseases.