Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases
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...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58149-y |
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| author | Yuji Yamamoto Yuya Shirai Kyuto Sonehara Shinichi Namba Takafumi Ojima Kenichi Yamamoto Ryuya Edahiro Ken Suzuki Akinori Kanai the BioBank Japan Project Yoshiya Oda Yutaka Suzuki Takayuki Morisaki Akira Narita Yoshito Takeda Gen Tamiya Masayuki Yamamoto Koichi Matsuda Atsushi Kumanogoh Toshimasa Yamauchi Takashi Kadowaki Yukinori Okada |
| author_facet | Yuji Yamamoto Yuya Shirai Kyuto Sonehara Shinichi Namba Takafumi Ojima Kenichi Yamamoto Ryuya Edahiro Ken Suzuki Akinori Kanai the BioBank Japan Project Yoshiya Oda Yutaka Suzuki Takayuki Morisaki Akira Narita Yoshito Takeda Gen Tamiya Masayuki Yamamoto Koichi Matsuda Atsushi Kumanogoh Toshimasa Yamauchi Takashi Kadowaki Yukinori Okada |
| author_sort | Yuji Yamamoto |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cabf62e4dc234423aa8e7efa2f3ee1db |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cabf62e4dc234423aa8e7efa2f3ee1db2025-08-20T01:47:29ZengNature PortfolioNature Communications2041-17232025-04-0116111810.1038/s41467-025-58149-yDissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseasesYuji Yamamoto0Yuya Shirai1Kyuto Sonehara2Shinichi Namba3Takafumi Ojima4Kenichi Yamamoto5Ryuya Edahiro6Ken Suzuki7Akinori Kanai8the BioBank Japan ProjectYoshiya Oda9Yutaka Suzuki10Takayuki Morisaki11Akira Narita12Yoshito Takeda13Gen Tamiya14Masayuki Yamamoto15Koichi Matsuda16Atsushi Kumanogoh17Toshimasa Yamauchi18Takashi Kadowaki19Yukinori Okada20Department of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoDepartment of Lipidomics, Graduate School of Medicine, The University of TokyoDepartment of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoDivision of Molecular Pathology, Institute of Medical Science, The University of TokyoTohoku Medical Megabank Organization, Tohoku UniversityDepartment of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of MedicineGraduate School of Medicine, Tohoku UniversityGraduate School of Medicine, Tohoku UniversityLaboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoDepartment of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of MedicineDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of TokyoDepartment of Statistical Genetics, Osaka University Graduate School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-58149-y |
| spellingShingle | Yuji Yamamoto Yuya Shirai Kyuto Sonehara Shinichi Namba Takafumi Ojima Kenichi Yamamoto Ryuya Edahiro Ken Suzuki Akinori Kanai the BioBank Japan Project Yoshiya Oda Yutaka Suzuki Takayuki Morisaki Akira Narita Yoshito Takeda Gen Tamiya Masayuki Yamamoto Koichi Matsuda Atsushi Kumanogoh Toshimasa Yamauchi Takashi Kadowaki Yukinori Okada Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases Nature Communications |
| title | Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| title_full | Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| title_fullStr | Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| title_full_unstemmed | Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| title_short | Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| title_sort | dissecting cross population polygenic heterogeneity across respiratory and cardiometabolic diseases |
| url | https://doi.org/10.1038/s41467-025-58149-y |
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