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

Anna L. Tyler, J. Matthew Mahoney, Mark P. Keller, Candice N. Baker, Margaret Gaca, Anuj Srivastava, Isabela Gerdes Gyuricza, Madeleine J. Braun, Nadia A. Rosenthal, Alan D. Attie, Gary A. Churchill () and Gregory W. Carter ()
Additional contact information
Anna L. Tyler: The Jackson Laboratory
J. Matthew Mahoney: The Jackson Laboratory
Mark P. Keller: Biochemistry Department
Candice N. Baker: The Jackson Laboratory
Margaret Gaca: The Jackson Laboratory
Anuj Srivastava: The Jackson Laboratory for Genomic Medicine
Isabela Gerdes Gyuricza: The Jackson Laboratory
Madeleine J. Braun: The Jackson Laboratory
Nadia A. Rosenthal: The Jackson Laboratory
Alan D. Attie: Biochemistry Department
Gary A. Churchill: The Jackson Laboratory
Gregory W. Carter: The Jackson Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61228-9

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DOI: 10.1038/s41467-025-61228-9

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