Shared and Unique Genetic Links Between Neuroticism and Gastrointestinal Tract Diseases

Objective. Association between neuroticism and gastrointestinal tract (GIT) diseases may not be attributable to the genetic overlaps between neuroticism and psychiatric disorders. We aim to explore the genetic links and mechanisms of neuroticism and GIT diseases. Materials and Methods. We obtained European genome-wide association data of neuroticism (n = 390,278) or subclusters (depressed, n = 357,957; worry, n = 348,219) and six GIT diseases: gastroesophageal reflux disease (GERD, n = 456,327), inflammatory bowel disease (IBD, n = 456,327), peptic ulcer disease (PUD, n = 456,327), irritable bowel syndrome (IBS, n = 486,601), Crohn's disease (CD, n = 20,883), and ulcerative colitis (UC, n = 21,895). We performed genetic correlation analysis (high-definition likelihood method and cross-trait linkage disequilibrium score regression), pairwise pleiotropic analysis, single nucleic acid polymorphism annotation, Bayesian colocalization, gene-level analysis, transcriptome-wide association analysis, and gene set enrichment analysis. Results. Neuroticism and its subclusters are associated with most GIT diseases (15 of 18 trait-pairs). GERD and PUD were highly correlated with depressed affect. We identified pleiotropic loci 11q23.2 (mapped gene: NCAM1/DRD2) and 18q12.2 (mapped gene: CELF4) in neuroticism and IBS/GERD, supporting the genetic overlap between neuroticism and depression. We found that 16q12.1 (mapped gene: NKD1/ZNF423/NOD2) and 2q37.1 (mapped gene: ATG16L1/SP140) are only highlighted in depressed/neuroticism CD, revealing pleiotropic loci with dissimilarities between neuroticism and different GIT diseases. MR analysis suggested that genetic liability to neuroticism is associated with increased risks of IBS, PUD, and GERD. Conclusion. Our findings document the genetic links between neuroticism and six GIT diseases, highlighting the genetic overlaps and heterogeneity between neuroticism and psychiatric disorders in the context of gastrointestinal disorders. Both the shared and unique pleiotropic loci identified between neuroticism and different GIT diseases could facilitate mechanistic understandings and may stimulate further translational implications.