IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58149-y.html
   My bibliography  Save this article

Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases

Author

Listed:
  • Yuji Yamamoto

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Yuya Shirai

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    Osaka University
    RIKEN Center for Integrative Medical Sciences)

  • Kyuto Sonehara

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

  • Shinichi Namba

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

  • Takafumi Ojima

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo
    Tohoku University)

  • Kenichi Yamamoto

    (Osaka University Graduate School of Medicine
    Osaka University
    Osaka University Graduate School of Medicine)

  • Ryuya Edahiro

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences)

  • Ken Suzuki

    (Osaka University Graduate School of Medicine
    The University of Tokyo)

  • Akinori Kanai

    (The University of Tokyo)

  • Yoshiya Oda

    (The University of Tokyo)

  • Yutaka Suzuki

    (The University of Tokyo)

  • Takayuki Morisaki

    (The University of Tokyo
    The University of Tokyo)

  • Akira Narita

    (Tohoku University)

  • Yoshito Takeda

    (Osaka University Graduate School of Medicine)

  • Gen Tamiya

    (Tohoku University
    RIKEN
    Tohoku University)

  • Masayuki Yamamoto

    (Tohoku University
    Tohoku University)

  • Koichi Matsuda

    (The University of Tokyo)

  • Atsushi Kumanogoh

    (Osaka University Graduate School of Medicine
    Osaka University
    Osaka University
    Osaka University)

  • Toshimasa Yamauchi

    (The University of Tokyo
    Japan Agency for Medical Research and Development—Core Research for Evolutional Science and Technology (AMED–CREST))

  • Takashi Kadowaki

    (The University of Tokyo
    Toranomon Hospital)

  • Yukinori Okada

    (Osaka University Graduate School of Medicine
    Osaka University
    RIKEN Center for Integrative Medical Sciences
    The University of Tokyo)

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.

Suggested Citation

  • 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, 2025. "Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58149-y
    DOI: 10.1038/s41467-025-58149-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58149-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58149-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tian Ge & Chia-Yen Chen & Yang Ni & Yen-Chen Anne Feng & Jordan W. Smoller, 2019. "Polygenic prediction via Bayesian regression and continuous shrinkage priors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Koen F. Dekkers & Roderick C. Slieker & Andreea Ioan-Facsinay & Maarten Iterson & M. Arfan Ikram & Marleen M. J. Greevenbroek & Jan H. Veldink & Lude Franke & Dorret I. Boomsma & P. Eline Slagboom & J, 2023. "Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    4. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    5. Yukinori Okada & Yukihide Momozawa & Saori Sakaue & Masahiro Kanai & Kazuyoshi Ishigaki & Masato Akiyama & Toshihiro Kishikawa & Yasumichi Arai & Takashi Sasaki & Kenjiro Kosaki & Makoto Suematsu & Ko, 2018. "Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    6. Go Sato & Yuya Shirai & Shinichi Namba & Ryuya Edahiro & Kyuto Sonehara & Tsuyoshi Hata & Mamoru Uemura & Koichi Matsuda & Yuichiro Doki & Hidetoshi Eguchi & Yukinori Okada, 2023. "Pan-cancer and cross-population genome-wide association studies dissect shared genetic backgrounds underlying carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. repec:plo:pmed00:1001779 is not listed on IDEAS
    8. Masato Akiyama & Kazuyoshi Ishigaki & Saori Sakaue & Yukihide Momozawa & Momoko Horikoshi & Makoto Hirata & Koichi Matsuda & Shiro Ikegawa & Atsushi Takahashi & Masahiro Kanai & Sadao Suzuki & Daisuke, 2019. "Characterizing rare and low-frequency height-associated variants in the Japanese population," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    9. Benjamin B. Sun & Joshua Chiou & Matthew Traylor & Christian Benner & Yi-Hsiang Hsu & Tom G. Richardson & Praveen Surendran & Anubha Mahajan & Chloe Robins & Steven G. Vasquez-Grinnell & Liping Hou & , 2023. "Plasma proteomic associations with genetics and health in the UK Biobank," Nature, Nature, vol. 622(7982), pages 329-338, October.
    10. Mitja I. Kurki & Juha Karjalainen & Priit Palta & Timo P. Sipilä & Kati Kristiansson & Kati M. Donner & Mary P. Reeve & Hannele Laivuori & Mervi Aavikko & Mari A. Kaunisto & Anu Loukola & Elisa Lahtel, 2023. "FinnGen provides genetic insights from a well-phenotyped isolated population," Nature, Nature, vol. 613(7944), pages 508-518, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yash Patel & Jean Shin & Eeva Sliz & Ariana Tang & Aniket Mishra & Rui Xia & Edith Hofer & Hema Sekhar Reddy Rajula & Ruiqi Wang & Frauke Beyer & Katrin Horn & Max Riedl & Jing Yu & Henry Völzke & Rob, 2024. "Genetic risk factors underlying white matter hyperintensities and cortical atrophy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Douglas P. Loesch & Manik Garg & Dorota Matelska & Dimitrios Vitsios & Xiao Jiang & Scott C. Ritchie & Benjamin B. Sun & Heiko Runz & Christopher D. Whelan & Rury R. Holman & Robert J. Mentz & Filipe , 2025. "Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    4. Kenichi Yamamoto & Kyuto Sonehara & Shinichi Namba & Takahiro Konuma & Hironori Masuko & Satoru Miyawaki & Yoichiro Kamatani & Nobuyuki Hizawa & Keiichi Ozono & Loic Yengo & Yukinori Okada, 2023. "Genetic footprints of assortative mating in the Japanese population," Nature Human Behaviour, Nature, vol. 7(1), pages 65-73, January.
    5. Andras Gezsi & Sandra Auwera & Hannu Mäkinen & Nora Eszlari & Gabor Hullam & Tamas Nagy & Sarah Bonk & Rubèn González-Colom & Xenia Gonda & Linda Garvert & Teemu Paajanen & Zsofia Gal & Kevin Kirchner, 2024. "Unique genetic and risk-factor profiles in clusters of major depressive disorder-related multimorbidity trajectories," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    6. Kenichi Yamamoto & Shinichi Namba & Kyuto Sonehara & Ken Suzuki & Saori Sakaue & Niall P. Cooke & Shinichi Higashiue & Shuzo Kobayashi & Hisaaki Afuso & Kosho Matsuura & Yojiro Mitsumoto & Yasuhiko Fu, 2024. "Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. Bingxin Zhao & Yujue Li & Zirui Fan & Zhenyi Wu & Juan Shu & Xiaochen Yang & Yilin Yang & Xifeng Wang & Bingxuan Li & Xiyao Wang & Carlos Copana & Yue Yang & Jinjie Lin & Yun Li & Jason L. Stein & Joa, 2024. "Eye-brain connections revealed by multimodal retinal and brain imaging genetics," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Chamlee Cho & Beomsu Kim & Dan Say Kim & Mi Yeong Hwang & Injeong Shim & Minku Song & Yeong Chan Lee & Sang-Hyuk Jung & Sung Kweon Cho & Woong-Yang Park & Woojae Myung & Bong-Jo Kim & Ron Do & Hyon K., 2024. "Large-scale cross-ancestry genome-wide meta-analysis of serum urate," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Sang‑Hyuk Jung & Haemin Kim & Young Mi Jung & Manu Shivakumar & Brenda Xiao & Jaeyoung Kim & Beomjin Jang & Jae-Seung Yun & Hong-Hee Won & Chan-Wook Park & Joong Shin Park & Jong Kwan Jun & Dokyoon Ki, 2025. "Healthy lifestyle reduces cardiovascular risk in women with genetic predisposition to hypertensive disorders of pregnancy," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    11. Yaohua Yang & Yaxin Chen & Shuai Xu & Xingyi Guo & Guochong Jia & Jie Ping & Xiang Shu & Tianying Zhao & Fangcheng Yuan & Gang Wang & Yufang Xie & Hang Ci & Hongmo Liu & Yawen Qi & Yongjun Liu & Dan L, 2024. "Integrating muti-omics data to identify tissue-specific DNA methylation biomarkers for cancer risk," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Go Sato & Yuya Shirai & Shinichi Namba & Ryuya Edahiro & Kyuto Sonehara & Tsuyoshi Hata & Mamoru Uemura & Koichi Matsuda & Yuichiro Doki & Hidetoshi Eguchi & Yukinori Okada, 2023. "Pan-cancer and cross-population genome-wide association studies dissect shared genetic backgrounds underlying carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Xiao-Yu He & Bang-Sheng Wu & Liu Yang & Yu Guo & Yue-Ting Deng & Ze-Yu Li & Chen-Jie Fei & Wei-Shi Liu & Yi-Jun Ge & Jujiao Kang & Jianfeng Feng & Wei Cheng & Qiang Dong & Jin-Tai Yu, 2024. "Genetic associations of protein-coding variants in venous thromboembolism," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    14. Xi Cao & Minghui Jiang & Yunlong Guan & Si Li & Chen Duan & Yan Gong & Yifan Kong & Zhonghe Shao & Hongji Wu & Xiangyang Yao & Bo Li & Miao Wang & Hua Xu & Xingjie Hao, 2025. "Trans-ancestry GWAS identifies 59 loci and improves risk prediction and fine-mapping for kidney stone disease," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    15. Alexander T. Williams & Jing Chen & Kayesha Coley & Chiara Batini & Abril Izquierdo & Richard Packer & Erik Abner & Stavroula Kanoni & David J. Shepherd & Robert C. Free & Edward J. Hollox & Nigel J. , 2023. "Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    16. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    17. Gökberk Alagöz & Else Eising & Yasmina Mekki & Giacomo Bignardi & Pierre Fontanillas & Michel G. Nivard & Michelle Luciano & Nancy J. Cox & Simon E. Fisher & Reyna L. Gordon, 2025. "The shared genetic architecture and evolution of human language and musical rhythm," Nature Human Behaviour, Nature, vol. 9(2), pages 376-390, February.
    18. Shahram Bahrami & Kaja Nordengen & Jaroslav Rokicki & Alexey A. Shadrin & Zillur Rahman & Olav B. Smeland & Piotr P. Jaholkowski & Nadine Parker & Pravesh Parekh & Kevin S. O’Connell & Torbjørn Elvsås, 2024. "The genetic landscape of basal ganglia and implications for common brain disorders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Jujiao Kang & Yue-Ting Deng & Bang-Sheng Wu & Wei-Shi Liu & Ze-Yu Li & Shitong Xiang & Liu Yang & Jia You & Xiaohong Gong & Tianye Jia & Jin-Tai Yu & Wei Cheng & Jianfeng Feng, 2024. "Whole exome sequencing analysis identifies genes for alcohol consumption," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Xingjie Hao & Zhonghe Shao & Ning Zhang & Minghui Jiang & Xi Cao & Si Li & Yunlong Guan & Chaolong Wang, 2023. "Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58149-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.