Investigating shared genetic architecture between inflammatory bowel diseases and primary biliary cholangitis
Wentao Huang,
Rui Jiang,
Sitao Li,
Ruijie Zeng,
Yang Li,
Yajie Zhang,
Shuangshuang Tong,
Yanlin Lyu,
Jiaxuan Wang,
Qizhou Lian,
Felix W. Leung,
Ruibang Luo,
Weihong Sha,
Hao Chen
Affiliations
Wentao Huang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
Rui Jiang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China
Sitao Li
Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat sen University, Guangzhou, China
Ruijie Zeng
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Yang Li
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Yajie Zhang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
Shuangshuang Tong
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Shantou University Medical College, Shantou, China
Yanlin Lyu
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Shantou University Medical College, Shantou, China
Jiaxuan Wang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Qizhou Lian
Faculty of Synthetic Biology, Shenzhen institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China
Felix W. Leung
Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA; University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA; Corresponding authors. Addresses: University of California Los Angeles, David Geffen School of Medicine, Los Angeles 90095, CA, USA (F.W. Leung); Department of Computer Science, The University of Hong Kong, Hong Kong (R. Luo); Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China (W. Sha and H. Chen).
Ruibang Luo
Department of Computer Science, The University of Hong Kong, Hong Kong; Corresponding authors. Addresses: University of California Los Angeles, David Geffen School of Medicine, Los Angeles 90095, CA, USA (F.W. Leung); Department of Computer Science, The University of Hong Kong, Hong Kong (R. Luo); Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China (W. Sha and H. Chen).
Weihong Sha
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Shantou University Medical College, Shantou, China; Corresponding authors. Addresses: University of California Los Angeles, David Geffen School of Medicine, Los Angeles 90095, CA, USA (F.W. Leung); Department of Computer Science, The University of Hong Kong, Hong Kong (R. Luo); Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China (W. Sha and H. Chen).
Hao Chen
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Shantou University Medical College, Shantou, China; Corresponding authors. Addresses: University of California Los Angeles, David Geffen School of Medicine, Los Angeles 90095, CA, USA (F.W. Leung); Department of Computer Science, The University of Hong Kong, Hong Kong (R. Luo); Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China (W. Sha and H. Chen).
Background & Aims: Inflammatory bowel disease (IBD) is commonly associated with extraintestinal complications, including autoimmune liver disease. The co-occurrence of IBD and primary biliary cholangitis (PBC) has been increasingly observed, but the underlying relationship between these conditions remains unclear. Methods: Using summary statistics from genome-wide association studies (GWAS), we investigated the causal effects between PBC and IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). We also analyzed the shared genetic architecture between IBD and PBC using data from GWAS, bulk-tissue RNA sequencing, and single cell RNA sequencing, and explored potential functional genes. Result: There was a strong positive genetic correlation between PBC and IBD (linkage disequilibrium score regression: rg = 0.2249, p = 3.38 × 10-5). Cross-trait analysis yielded 10 shared-risk single nucleotide polymorphisms (SNPs), as well as nine novel SNPs, which were associated with both traits. Using Mendelian randomization, a stable causal effect was established of PBC on IBD. Genetically predicted PBC was found to have a risk effect on IBD (1.105; 95% CI: 1.058–1.15; p = 1.16 × 10-10), but not vice versa. Shared tissue-specific heritability enrichment was identified for PBC and IBD (including CD and UC) in lung, spleen, and whole-blood samples. Furthermore, shared enrichment was observed of specific cell types (T cells, B cells, and natural killer cells) and their subtypes. Nine functional genes were identified based on summary statistics-based Mendelian randomization. Conclusions: This study detected shared genetic architecture between IBD and PBC and demonstrated a stable causal relationship of genetically predicted PBC on the risk of IBD. These findings shed light on the biological basis of comorbidity between IBD and PBC, and have important implications for intervention and treatment targets of these two diseases simultaneously. Impact and Implications: The discovery of novel shared single nucleotide polymorphisms (SNPs) and functional genes provides insights into the common targets between inflammatory bowel disease (IBD) and primary biliary cholangitis (PBC), serving as a basis for new drug development and contributing to the study of disease pathogenesis. Additionally, the established significant causality and genetic correlation underscore the importance of clinical intervention in preventing the comorbidity of IBD and PBC. The enrichment of SNP heritability in specific tissues and cell types reveals the role of immune factors in the potential disease mechanisms shared between IBD and PBC. This stimulates further research on potential interventions and could lead to the development of new targets for immune-based therapies.
