IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58248-w.html
   My bibliography  Save this article

A genome-wide cross-trait analysis characterizes the shared genetic architecture between lung and gastrointestinal diseases

Author

Listed:
  • Dongfang You

    (Nanjing Medical University
    The First Affiliated Hospital of Nanjing Medical University)

  • Yaqian Wu

    (Nanjing Medical University)

  • Mengyi Lu

    (Nanjing Medical University)

  • Fang Shao

    (Nanjing Medical University)

  • Yingdan Tang

    (Nanjing Medical University)

  • Sisi Liu

    (Nanjing Medical University)

  • Liya Liu

    (Ningbo University)

  • Zewei Zhou

    (Nanjing Medical University)

  • Ruyang Zhang

    (Nanjing Medical University)

  • Sipeng Shen

    (Nanjing Medical University)

  • Theis Lange

    (University of Copenhagen)

  • Hongyang Xu

    (Wuxi People’s Hospital Affiliated to Nanjing Medical University)

  • Hongxia Ma

    (Nanjing Medical University
    Nanjing Medical University)

  • Yongmei Yin

    (The First Affiliated Hospital of Nanjing Medical University)

  • Hongbing Shen

    (Nanjing Medical University
    Nanjing Medical University)

  • Feng Chen

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • David C. Christiani

    (Harvard T.H. Chan School of Public Health)

  • Guangfu Jin

    (Nanjing Medical University
    Nanjing Medical University)

  • Yang Zhao

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

Abstract

Lung and gastrointestinal diseases often occur together, leading to more adverse health outcomes than when a disease of one of these systems occurs alone. However, the potential genetic mechanisms underlying lung-gastrointestinal comorbidities remain unclear. Here, we leverage lung and gastrointestinal trait data from individuals of European, East Asian and African ancestries, to perform a large-scale genetic cross trait analysis, followed by functional annotation and Mendelian randomization analysis to explore the genetic mechanisms involved in the development of lung-gastrointestinal comorbidities. Notably, we find significant genetic correlations between 27 trait pairs among the European population. The highest correlation is between chronic bronchitis and peptic ulcer disease. At the variant level, we identify 42 candidate pleiotropic genetic variants (3 of them previously uncharacterized) in 14 trait pairs by integrating cross-trait meta-analysis, fine-mapping and colocalization analyses. We also find 66 candidate pleiotropic genes, most of which were enriched in immune or inflammatory response-related activities. Causal inference approaches result in 4 potential lung-gastrointestinal associations. Introducing the gut microbiota as a variable establishes a relationship between the genus Parasutterella, gastro-oesophageal reflux disease and asthma. In summary, our findings highlight the genetic relationship between lung and gastrointestinal diseases, providing insights into the genetic mechanisms underlying the development of lung gastrointestinal comorbidities.

Suggested Citation

  • Dongfang You & Yaqian Wu & Mengyi Lu & Fang Shao & Yingdan Tang & Sisi Liu & Liya Liu & Zewei Zhou & Ruyang Zhang & Sipeng Shen & Theis Lange & Hongyang Xu & Hongxia Ma & Yongmei Yin & Hongbing Shen &, 2025. "A genome-wide cross-trait analysis characterizes the shared genetic architecture between lung and gastrointestinal diseases," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58248-w
    DOI: 10.1038/s41467-025-58248-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58248-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58248-w?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. Yingbo Huang & Yuting Shan & Weijie Zhang & Adam M. Lee & Feng Li & Barbara E. Stranger & R. Stephanie Huang, 2023. "Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Xia Jiang & Hilary K. Finucane & Fredrick R. Schumacher & Stephanie L. Schmit & Jonathan P. Tyrer & Younghun Han & Kyriaki Michailidou & Corina Lesseur & Karoline B. Kuchenbaecker & Joe Dennis & David, 2019. "Publisher Correction: Shared heritability and functional enrichment across six solid cancers," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    3. Rongtao Jiang & Stephanie Noble & Matthew Rosenblatt & Wei Dai & Jean Ye & Shu Liu & Shile Qi & Vince D. Calhoun & Jing Sui & Dustin Scheinost, 2024. "The brain structure, inflammatory, and genetic mechanisms mediate the association between physical frailty and depression," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Shufen Zheng & Philip S. Tsao & Cuiping Pan, 2024. "Abdominal aortic aneurysm and cardiometabolic traits share strong genetic susceptibility to lipid metabolism and inflammation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Helian Feng & Nicholas Mancuso & Alexander Gusev & Arunabha Majumdar & Megan Major & Bogdan Pasaniuc & Peter Kraft, 2021. "Leveraging expression from multiple tissues using sparse canonical correlation analysis and aggregate tests improves the power of transcriptome-wide association studies," PLOS Genetics, Public Library of Science, vol. 17(4), pages 1-21, April.
    6. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    7. Xia Jiang & Hilary K. Finucane & Fredrick R. Schumacher & Stephanie L. Schmit & Jonathan P. Tyrer & Younghun Han & Kyriaki Michailidou & Corina Lesseur & Karoline B. Kuchenbaecker & Joe Dennis & David, 2019. "Shared heritability and functional enrichment across six solid cancers," Nature Communications, Nature, vol. 10(1), pages 1-23, December.
    8. 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.
    9. 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. "Author Correction: FinnGen provides genetic insights from a well-phenotyped isolated population," Nature, Nature, vol. 615(7952), pages 19-19, March.
    10. Yeda Wu & Graham K. Murray & Enda M. Byrne & Julia Sidorenko & Peter M. Visscher & Naomi R. Wray, 2021. "GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    11. Dongjun Chung & Can Yang & Cong Li & Joel Gelernter & Hongyu Zhao, 2014. "GPA: A Statistical Approach to Prioritizing GWAS Results by Integrating Pleiotropy and Annotation," PLOS Genetics, Public Library of Science, vol. 10(11), pages 1-14, November.
    12. Stasa Stankovic & Saleh Shekari & Qin Qin Huang & Eugene J. Gardner & Erna V. Ivarsdottir & Nick D. L. Owens & Nasim Mavaddat & Ajuna Azad & Gareth Hawkes & Katherine A. Kentistou & Robin N. Beaumont , 2024. "Genetic links between ovarian ageing, cancer risk and de novo mutation rates," Nature, Nature, vol. 633(8030), pages 608-614, September.
    13. Cathie Sudlow & John Gallacher & Naomi Allen & Valerie Beral & Paul Burton & John Danesh & Paul Downey & Paul Elliott & Jane Green & Martin Landray & Bette Liu & Paul Matthews & Giok Ong & Jill Pell &, 2015. "UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age," PLOS Medicine, Public Library of Science, vol. 12(3), pages 1-10, March.
    14. Thomas S. Wingo & Yue Liu & Ekaterina S. Gerasimov & Selina M. Vattathil & Meghan E. Wynne & Jiaqi Liu & Adriana Lori & Victor Faundez & David A. Bennett & Nicholas T. Seyfried & Allan I. Levey & Aliz, 2022. "Shared mechanisms across the major psychiatric and neurodegenerative diseases," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    15. 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. Hui Chen & Zeyang Wang & Lihai Gong & Qixuan Wang & Wenyan Chen & Jia Wang & Xuelian Ma & Ruofan Ding & Xing Li & Xudong Zou & Mireya Plass & Cheng Lian & Ting Ni & Gong-Hong Wei & Wei Li & Lin Deng &, 2024. "A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Shuai Yuan & Jie Chen & Jiawei Geng & Sizheng Steven Zhao & James Yarmolinsky & Elizabeth V. Arkema & Sarah Abramowitz & Michael G. Levin & Kostas K. Tsilidis & Stephen Burgess & Scott M. Damrauer & S, 2025. "GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    3. 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.
    4. 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.
    5. Jonathan Mitchell & Niedzica Camacho & Patrick Shea & Konrad H. Stopsack & Vijai Joseph & Oliver S. Burren & Ryan S. Dhindsa & Abhishek Nag & Jacob E. Berchuck & Amanda O’Neill & Ali Abbasi & Anthony , 2025. "Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    6. 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.
    7. Priya Gupta & Marco Galimberti & Yue Liu & Sarah Beck & Aliza Wingo & Thomas Wingo & Keyrun Adhikari & Henry R. Kranzler & Murray B. Stein & Joel Gelernter & Daniel F. Levey, 2024. "A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology," Nature Human Behaviour, Nature, vol. 8(11), pages 2235-2249, November.
    8. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Hongru Li & Jingyi Zhao & Jinglan Dai & Dongfang You & Yang Zhao & David C. Christiani & Feng Chen & Sipeng Shen, 2025. "Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    10. 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.
    11. 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.
    12. Javier Botey-Bataller & Hedwig D. Vrijmoeth & Jeanine Ursinus & Bart-Jan Kullberg & Cees C. Wijngaard & Hadewych Hofstede & Ahmed Alaswad & Manoj K. Gupta & Lennart M. Roesner & Jochen Huehn & Thomas , 2024. "A comprehensive genetic map of cytokine responses in Lyme borreliosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    13. Ichcha Manipur & Guillermo Reales & Jae Hoon Sul & Myung Kyun Shin & Simonne Longerich & Adrian Cortes & Chris Wallace, 2024. "CoPheScan: phenome-wide association studies accounting for linkage disequilibrium," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    14. William R. Reay & Dylan J. Kiltschewskij & Maria A. Biase & Zachary F. Gerring & Kousik Kundu & Praveen Surendran & Laura A. Greco & Erin D. Clarke & Clare E. Collins & Alison M. Mondul & Demetrius Al, 2024. "Genetic influences on circulating retinol and its relationship to human health," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    15. Santiago Diaz-Torres & Samantha Sze-Yee Lee & Luis M. García-Marín & Adrian I. Campos & Garreth Lingham & Jue-Sheng Ong & David A. Mackey & Kathryn P. Burdon & Michael Hunter & Xianjun Dong & Stuart M, 2024. "Uncovering genetic loci and biological pathways associated with age-related cataracts through GWAS meta-analysis," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    16. Xuening Zhang & Hao Zhao & Meng Wan & Jinyu Man & Tongchao Zhang & Xiaorong Yang & Ming Lu, 2025. "Associations of 2923 plasma proteins with incident inflammatory bowel disease in a prospective cohort study and genetic analysis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    17. 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.
    18. Salim Megat & Christine Marques & Marina Hernán-Godoy & Chantal Sellier & Geoffrey Stuart-Lopez & Sylvie Dirrig-Grosch & Charlotte Gorin & Aurore Brunet & Mathieu Fischer & Céline Keime & Pascal Kessl, 2025. "CREB3 gain of function variants protect against ALS," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    19. 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.
    20. 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.

    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_s41467-025-58248-w. 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.