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

• Published in: Nature communications Vol. 16; no. 1; pp. 5507 - 21
• Main Authors: Tyler, Anna L., Mahoney, J. Matthew, Keller, Mark P., Baker, Candice N., Gaca, Margaret, Srivastava, Anuj, Gyuricza, Isabela Gerdes, Braun, Madeleine J., Rosenthal, Nadia A., Attie, Alan D., Churchill, Gary A., Carter, Gregory W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/199; 631/443/319/1642/393; 631/553/2490; Animals; Body fat; Datasets; Diabetes; Dimensional analysis; Fasting; Female; Females; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene regulation; Genetic effects; Genetic variability; Genomes; Glucose; Heritability; Humanities and Social Sciences; Humans; Insulin; Male; Males; Metabolic Diseases - genetics; Metabolic disorders; Mice; multidisciplinary; Multifactorial Inheritance - genetics; Musculoskeletal system; Obesity; Obesity - genetics; Obesity - metabolism; Phenotype; Physiology; Quantitative Trait, Heritable; Regression analysis; Science; Science (multidisciplinary); Transcriptome - genetics; Transcriptomes; Variability
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-61228-9

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 combine 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 identify a composite transcriptome signature that summarizes genetic effects on gene expression and explains 30% of the variation across all metabolic traits. The signature is heritable, interpretable in biological terms, and predicts obesity status from gene expression in an independently derived mouse cohort and multiple human studies. Transcripts contributing most strongly to this composite mediator frequently have complex, distal regulation distributed throughout the genome. These results suggest that trait-relevant variation in transcription is largely distally regulated, but is nonetheless identifiable, interpretable, and translatable across species. Distal gene regulation is increasingly recognised as a major contributor to complex trait variability. Here, the authors show that a heritable, biologically interpretable transcriptome signature driven by distal regulation predicts metabolic traits across mice and humans.