Document Type
Article
Publication Date
7-1-2025
Original Citation
Tyler AL,
Mahoney J,
Keller M,
Baker C,
Gaca M,
Srivastava A,
Gerdes Gyuricza I,
Braun M,
Rosenthal N,
Attie A,
Churchill G,
Carter GW.
Transcripts with high distal heritability mediate genetic effects on complex metabolic traits. Nat Commun. 2025;16(1):5507.
Keywords
JGM, JMG, SS1, Animals, Mice, Transcriptome, Obesity, Humans, Male, Gene Expression Regulation, Gene Expression Profiling, Multifactorial Inheritance, Female, Metabolic Diseases, Phenotype, Quantitative Trait, Heritable
JAX Source
Nat Commun. 2025;16(1):5507.
ISSN
2041-1723
PMID
40595617
DOI
https://doi.org/10.1038/s41467-025-61228-9
Grant
R01GM115518 to G. W. C., and R01GM141309 to J.M.
Abstract
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.