Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis

Jing Wang; Guang-Yu Luo; Tian Tian; Yu-Qiang Zhao; Shi-Yin Meng; Jun-Hua Wu; Wen-Xiu Han; Bin Deng; Jing Ni

doi:10.1017/S0033291724000771

Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis

Psychol Med. 2024 Apr 2:1-11. doi: 10.1017/S0033291724000771. Online ahead of print.

Authors

Jing Wang¹, Guang-Yu Luo², Tian Tian¹, Yu-Qiang Zhao¹, Shi-Yin Meng¹, Jun-Hua Wu³, Wen-Xiu Han⁴, Bin Deng², Jing Ni¹

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China.
² Department of Gastroenterology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
³ Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, China.
⁴ Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

PMID: 38563283
DOI: 10.1017/S0033291724000771

Abstract

Background: The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear.

Methods: By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders.

Results: SCZ genetically correlated with IBD (r_g = 0.14, p = 3.65 × 10⁻⁹), UC (r_g = 0.15, p = 4.88 × 10⁻⁸), and CD (r_g = 0.12, p = 2.27 × 10⁻⁶), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07–1.15, p = 1.85 × 10⁻⁶). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06–1.16, p = 1.34 × 10⁻⁶) or BMI (OR 1.11, 95% CI 1.04–1.18, p = 1.84 × 10⁻³).

Conclusions: We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

Keywords: cross-trait meta-analysis; genetic correlation; inflammatory bowel disease; mendelian randomization; schizophrenia.