TY - JOUR
T1 - Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases
AU - The BioBank Japan Project
AU - Yamamoto, Yuji
AU - Shirai, Yuya
AU - Sonehara, Kyuto
AU - Namba, Shinichi
AU - Ojima, Takafumi
AU - Yamamoto, Kenichi
AU - Edahiro, Ryuya
AU - Suzuki, Ken
AU - Kanai, Akinori
AU - Okada, Yukinori
AU - Morisaki, Takayuki
AU - Matsuda, Koichi
AU - Oda, Yoshiya
AU - Suzuki, Yutaka
AU - Morisaki, Takayuki
AU - Narita, Akira
AU - Takeda, Yoshito
AU - Tamiya, Gen
AU - Yamamoto, Masayuki
AU - Matsuda, Koichi
AU - Kumanogoh, Atsushi
AU - Yamauchi, Toshimasa
AU - Kadowaki, Takashi
AU - Okada, Yukinori
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-025-58149-y
DO - 10.1038/s41467-025-58149-y
M3 - Article
C2 - 40295474
AN - SCOPUS:105004331178
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3765
ER -