Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal tract disorders

Siquan Zhou; Jing Zi; Yifan Hu; Xiaoyu Wang; Guo Cheng; Jingyuan Xiong

doi:10.1016/j.jad.2025.01.048

Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal tract disorders

J Affect Disord. 2025 Jan 10:374:84-90. doi: 10.1016/j.jad.2025.01.048. Online ahead of print.

Authors

Siquan Zhou¹, Jing Zi¹, Yifan Hu¹, Xiaoyu Wang², Guo Cheng³, Jingyuan Xiong⁴

Affiliations

¹ Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
² Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital, Sichuan University, Chengdu, China.
³ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital, Sichuan University, Chengdu, China. Electronic address: gcheng@scu.edu.cn.
⁴ Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu 610041, China. Electronic address: jzx0004@tigermail.auburn.edu.

PMID: 39800072
DOI: 10.1016/j.jad.2025.01.048

Abstract

Background: Major depressive disorder (MDD) is associated with gastrointestinal tract (GIT) disorders, while genetic correlation, pleiotropic loci and shared risk genes remain to be explored.

Methods: Leveraging genome-wide association study statistics for MDD (n = 170,756), peptic ulcer disease (PUD; n = 16,666), gastroesophageal reflux disease (GORD; n = 54,854), PUD and/or GORD and/or medications (PGM; n = 90,175), irritable bowel syndrome (IBS; n = 28,518), and inflammatory bowel disease (IBD; n = 7045), we determined global and local genetic correlations, identified pleiotropic loci, performed gene-level evaluations, and inferred causal associations using bidirectional Mendelian randomization.

Results: We found global correlation of MDD with PUD (r_g = 0.444, P = 3.135 × 10^-24), GORD (r_g = 0.459, P = 2.568 × 10^-65), PGM (r_g = 0.498, P = 6.094 × 10^-114), IBS (r_g = 0.621, P = 2.483 × 10^-63), and IBD (r_g = 0.171, P = 1.824 × 10^-5). We identified 12 locally correlated regions between MDD and GIT disorders except for IBD, and one shared region (chr11:111985737-113,103,996) for PGM, GORD, and IBS. We found one pleiotropic locus for PUD, 12 for GORD, 30 for PGM, eight for IBS, and seven for IBD, and five shared loci (rs138786869, rs2284189, rs3130063, rs35789010, rs7568369) for GORD and PGM. We respectively observed 14 and 20 overlapping genes for MDD-GORD and MDD-PGM. We showed genetic liabilities to GORD, PGM, and IBS causally increase MDD risk, while all reverse causalities are significant.

Conclusions: Our work identifies genetic architectures shared between MDD and GIT disorders, contributes genetic insights to understand depression in the context of gut-brain interactions, and provides potential targets to treat gastrointestinal symptoms in depressive patients.

Keywords: Causal inference; Co-morbidity; Cross-trait meta-analysis; Gastrointestinal tract disorders; Genetic architecture; Major depression disorder.