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

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, Feng Chen, David C. Christiani, Guangfu Jin () and Yang Zhao ()
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Dongfang You: 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
Yongmei Yin: The First Affiliated Hospital of Nanjing Medical University
Hongbing Shen: Nanjing Medical University
Feng Chen: Nanjing Medical University
David C. Christiani: Harvard T.H. Chan School of Public Health
Guangfu Jin: Nanjing Medical University
Yang Zhao: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58248-w

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