Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-04-28 DOI:10.1038/s41467-025-58149-y

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, Yukinori Okada

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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.

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呼吸和心脏代谢疾病的跨人群多基因异质性剖析

多重发病的生物学机制仍然难以捉摸。为了分析人群中12个复杂性状的多发病多基因异质性，我们利用了232,987名东亚个体（日本生物银行的第一和第二队列）和751,051名欧洲个体（英国生物银行和FinnGen）的全基因组关联研究（GWAS）的生物银行资源。呼吸和心脏代谢疾病、类风湿关节炎和吸烟的交叉性状分析发现东亚个体呼吸和心脏代谢疾病之间存在负相关的遗传关系，与欧洲个体的正相关相反。将全基因组多基因风险评分（PRS）与325个血液代谢组和2917个蛋白质组生物标志物相关联，支持东亚个体的负交叉性状遗传相关性。贝叶斯通路PRS分析显示哮喘和血脂异常在过氧化物酶体增殖物激活受体基因组中呈负相关。该途径表明，在肺单细胞rna测序数据集的富集分析中，细胞类型特异性存在异质性。我们的研究强调了多重疾病中免疫代谢功能障碍的异质性多效性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.