Genome-wide association study of gastrointestinal disorders reinforces the link between the digestive tract and the nervous system

Abstract

Genetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 individuals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs associated with PUD at or near genes MUC1, FUT2, PSCA and CCKBR, for which there are previously established roles in Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-directional causality (the risk of GORD in liability to major depression and the risk of major depression in liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS than between these disorders and IBD is reported. These findings advance understanding the role of genetic variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous system and the gastrointestinal tract.