Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases

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 Narita, Yoshito Takeda, Gen Tamiya, Masayuki Yamamoto, Koichi Matsuda, Atsushi Kumanogoh, Toshimasa Yamauchi (), Takashi Kadowaki () and Yukinori Okada ()
Additional contact information
Yuji Yamamoto: Osaka University Graduate School of Medicine
Yuya Shirai: Osaka University Graduate School of Medicine
Kyuto Sonehara: Osaka University Graduate School of Medicine
Shinichi Namba: Osaka University Graduate School of Medicine
Takafumi Ojima: Osaka University Graduate School of Medicine
Kenichi Yamamoto: Osaka University Graduate School of Medicine
Ryuya Edahiro: Osaka University Graduate School of Medicine
Ken Suzuki: Osaka University Graduate School of Medicine
Akinori Kanai: The University of Tokyo
Yoshiya Oda: The University of Tokyo
Yutaka Suzuki: The University of Tokyo
Takayuki Morisaki: The University of Tokyo
Akira Narita: Tohoku University
Yoshito Takeda: Osaka University Graduate School of Medicine
Gen Tamiya: Tohoku University
Masayuki Yamamoto: Tohoku University
Koichi Matsuda: The University of Tokyo
Atsushi Kumanogoh: Osaka University Graduate School of Medicine
Toshimasa Yamauchi: The University of Tokyo
Takashi Kadowaki: The University of Tokyo
Yukinori Okada: Osaka University Graduate School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58149-y

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