Yamamoto Yuji, Shirai Yuya, Sonehara Kyuto, Namba Shinichi, Ojima Takafumi, Yamamoto Kenichi, Edahiro Ryuya, Suzuki Ken, Kanai Akinori, Oda Yoshiya, Suzuki Yutaka, Morisaki Takayuki, Narita Akira, Takeda Yoshito, Tamiya Gen, Yamamoto Masayuki, Matsuda Koichi, Kumanogoh Atsushi, Yamauchi Toshimasa, Kadowaki Takashi, Okada Yukinori
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
Nat Commun. 2025 Apr 28;16(1):3765. doi: 10.1038/s41467-025-58149-y.
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.
多病共存背后的生物学机制仍不明确。为剖析不同人群中12种复杂性状下多病共存的多基因异质性，我们利用了生物样本库中全基因组关联研究（GWAS）的资源，涉及232,987名东亚个体（日本生物银行的第1和第2队列）以及751,051名欧洲个体（英国生物银行和芬兰基因库）。对呼吸道和心脏代谢疾病、类风湿性关节炎以及吸烟进行跨性状分析发现，东亚个体中呼吸道疾病和心脏代谢疾病之间存在负向遗传相关性，这与欧洲个体中的正向关联相反。将全基因组多基因风险评分（PRS）与325种血液代谢组和2917种蛋白质组生物标志物相关联，支持了东亚个体中的负向跨性状遗传相关性。贝叶斯通路PRS分析揭示了在过氧化物酶体增殖物激活受体基因集中哮喘与血脂异常之间存在负向关联。该通路在肺单细胞RNA测序数据集的富集分析中提示了细胞类型特异性的异质性。我们的研究突出了多病共存中免疫代谢功能障碍的异质性多效性。
