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

Author

Listed:
  • 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
    Imperial College)

  • Alan D. Attie

    (Biochemistry Department)

  • Gary A. Churchill

    (The Jackson Laboratory)

  • Gregory W. Carter

    (The Jackson Laboratory)

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.

Suggested Citation

  • 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. C, 2025. "Transcripts with high distal heritability mediate genetic effects on complex metabolic traits," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61228-9
    DOI: 10.1038/s41467-025-61228-9
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    References listed on IDEAS

    as
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