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Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases

Author

Listed:
  • Yuji Yamamoto

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Yuya Shirai

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    Osaka University
    RIKEN Center for Integrative Medical Sciences)

  • Kyuto Sonehara

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

  • Shinichi Namba

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

  • Takafumi Ojima

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo
    Tohoku University)

  • Kenichi Yamamoto

    (Osaka University Graduate School of Medicine
    Osaka University
    Osaka University Graduate School of Medicine)

  • Ryuya Edahiro

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Ken Suzuki

    (Osaka University Graduate School of Medicine
    The University of Tokyo)

  • Akinori Kanai

    (The University of Tokyo)

  • Yoshiya Oda

    (The University of Tokyo)

  • Yutaka Suzuki

    (The University of Tokyo)

  • Takayuki Morisaki

    (The University of Tokyo
    The University of Tokyo)

  • Akira Narita

    (Tohoku University)

  • Yoshito Takeda

    (Osaka University Graduate School of Medicine)

  • Gen Tamiya

    (Tohoku University
    RIKEN
    Tohoku University)

  • Masayuki Yamamoto

    (Tohoku University
    Tohoku University)

  • Koichi Matsuda

    (The University of Tokyo)

  • Atsushi Kumanogoh

    (Osaka University Graduate School of Medicine
    Osaka University
    Osaka University
    Osaka University)

  • Toshimasa Yamauchi

    (The University of Tokyo
    Japan Agency for Medical Research and Development—Core Research for Evolutional Science and Technology (AMED–CREST))

  • Takashi Kadowaki

    (The University of Tokyo
    Toranomon Hospital)

  • Yukinori Okada

    (Osaka University Graduate School of Medicine
    Osaka University
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

Abstract

Biological mechanisms underlying multimorbidity remain elusive. To dissect the polygenic heterogeneity of multimorbidity in twelve complex traits across populations, we leveraged biobank resources of genome-wide association studies (GWAS) for 232,987 East Asian individuals (the 1st and 2nd cohorts of BioBank Japan) and 751,051 European individuals (UK Biobank and FinnGen). Cross-trait analyses of respiratory and cardiometabolic diseases, rheumatoid arthritis, and smoking identified negative genetic correlations between respiratory and cardiometabolic diseases in East Asian individuals, opposite from the positive associations in European individuals. Associating genome-wide polygenic risk scores (PRS) with 325 blood metabolome and 2917 proteome biomarkers supported the negative cross-trait genetic correlations in East Asian individuals. Bayesian pathway PRS analysis revealed a negative association between asthma and dyslipidemia in a gene set of peroxisome proliferator-activated receptors. The pathway suggested heterogeneity of cell type specificity in the enrichment analysis of the lung single-cell RNA-sequencing dataset. Our study highlights the heterogeneous pleiotropy of immunometabolic dysfunction in multimorbidity.

Suggested Citation

  • Yuji Yamamoto & Yuya Shirai & Kyuto Sonehara & Shinichi Namba & Takafumi Ojima & Kenichi Yamamoto & Ryuya Edahiro & Ken Suzuki & Akinori Kanai & Yoshiya Oda & Yutaka Suzuki & Takayuki Morisaki & Akira, 2025. "Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58149-y
    DOI: 10.1038/s41467-025-58149-y
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