Investigating the shared genetic architecture of post-traumatic stress disorder and gastrointestinal tract disorders: a genome-wide cross-trait analysis

Siquan Zhou; Hang Luo; Ye Tian; Haoqi Li; Yaxian Zeng; Xiaoyu Wang; Shufang Shan; Jingyuan Xiong; Guo Cheng

doi:10.1017/S0033291723001423

Investigating the shared genetic architecture of post-traumatic stress disorder and gastrointestinal tract disorders: a genome-wide cross-trait analysis

Psychol Med. 2023 Dec;53(16):7627-7635. doi: 10.1017/S0033291723001423. Epub 2023 May 23.

Authors

Siquan Zhou^{1

2}, Hang Luo¹, Ye Tian¹, Haoqi Li¹, Yaxian Zeng¹, Xiaoyu Wang², Shufang Shan², Jingyuan Xiong¹, Guo Cheng²

Affiliations

¹ West China School of Public Health and West China Fourth Hospital, Healthy Food Evaluation Research Center, 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, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.

PMID: 37218628
DOI: 10.1017/S0033291723001423

Abstract

Background: Observational studies suggest a correlation between post-traumatic stress disorder (PTSD) and gastrointestinal tract (GIT) disorders. However, the genetic overlap, causal relationships, and underlining mechanisms between PTSD and GIT disorders were absent.

Methods: We obtained genome-wide association study statistics for PTSD (23 212 cases, 151 447 controls), peptic ulcer disease (PUD; 16 666 cases, 439 661 controls), gastroesophageal reflux disease (GORD; 54 854 cases, 401 473 controls), PUD and/or GORD and/or medications (PGM; 90 175 cases, 366 152 controls), irritable bowel syndrome (IBS; 28 518 cases, 426 803 controls), and inflammatory bowel disease (IBD; 7045 cases, 449 282 controls). We quantified genetic correlations, identified pleiotropic loci, and performed multi-marker analysis of genomic annotation, fast gene-based association analysis, transcriptome-wide association study analysis, and bidirectional Mendelian randomization analysis.

Results: PTSD globally correlates with PUD (r_g = 0.526, p = 9.355 × 10^-7), GORD (r_g = 0.398, p = 5.223 × 10^-9), PGM (r_g = 0.524, p = 1.251 × 10^-15), and IBS (r_g = 0.419, p = 8.825 × 10^-6). Cross-trait meta-analyses identify seven genome-wide significant loci between PTSD and PGM (rs13107325, rs1632855, rs1800628, rs2188100, rs3129953, rs6973700, and rs73154693); three between PTSD and GORD (rs13107325, rs1632855, and rs3132450); one between PTSD and IBS/IBD (rs4937872 and rs114969413, respectively). Proximal pleiotropic genes are mainly enriched in immune response regulatory pathways, and in brain, digestive, and immune systems. Gene-level analyses identify five candidates: ABT1, BTN3A2, HIST1H3J, ZKSCAN4, and ZKSCAN8. We found significant causal effects of GORD, PGM, IBS, and IBD on PTSD. We observed no reverse causality of PTSD with GIT disorders, except for GORD.

Conclusions: PTSD and GIT disorders share common genetic architectures. Our work offers insights into the biological mechanisms, and provides genetic basis for translational research studies.

Keywords: Causal inference; Mendelian randomization; cross-trait meta-analysis; gastroesophageal reflux disease; gastrointestinal tract disorders; inflammatory bowel disease; irritable bowel syndrome; peptic ulcer disease; post-traumatic stress disorder; shared genetic architecture.

MeSH terms

Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases*
Irritable Bowel Syndrome* / genetics
Mendelian Randomization Analysis
Polymorphism, Single Nucleotide
Stress Disorders, Post-Traumatic* / genetics