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

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.