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

Abstract

11Genetic factors are recognized to contribute to common gastrointestinal (GI) diseases such as gastro-12 oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS) and 13 inflammatory bowel disease (IBD). We conducted genome-wide association analyses based on 456,414 14 individuals and identified 27 independent and significant loci for GORD, PUD and IBS, including SNPs 15 associated with PUD at or near genes MUC1, FUT2, PSCA and CCKBR, for which there are previously 16 established roles in Helicobacter pylori infection, response to counteract infection-related damage, gastric acid 17 secretion and gastrointestinal motility. Post-GWAS analyses implicate putative functional links between the 18 nervous system and gastrointestinal tract for GORD, PUD and IBS, including the central nervous system, the 19 enteric nervous system and their connection. Mendelian Randomisation analyses imply potentially bi-20 directional causality (the risk of GORD in liability to major depression and the risk of major depression in 21 liability to GORD) or pleiotropic effect between them. A stronger genetic similarity among GORD, PUD and IBS 22 than between these disorders and IBD is reported. These findings advance understanding the role of genetic 23 variants in the etiology of GORD, PUD and IBS and add biological insights into the link between the nervous 24 system and the gastrointestinal tract. 25 1Gastrointestinal (GI) diseases are highly prevalent in western countries. They use substantial health care 2 resources, are a heavy societal economic burden 1,2 , and impact the quality of life of those affected. Common 3 GI disorders include gastro-oesophageal reflux disease (GORD), peptic ulcer disease (PUD), irritable bowel 4 syndrome (IBS) and inflammatory bowel disease (IBD). In GORD, the stomach contents leak back from the 5 stomach into the esophagus 3 . PUD involves breaks (ulcers) in the inner lining of the digestive tract, usually 6 located in the stomach or proximal duodenum. IBS is a chronic functional disorder of the GI system. Patients 7 with IBS often manifest abdominal pain and altered bowel habit, with either predominantly diarrhea, 8 constipation or both. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), which are chronic idiopathic 9 disorders causing inflammation of the GI tract. 10 GORD is a multifactorial disorder and is more common in individuals with obesity and hiatal hernia 4 . 11Lifetime risk estimates of GORD have a wide range (9%-26%), with a sample size-weighted mean of 15% 5 . An 12 increase in the prevalence of GORD since 1995 has been reported 5 . PUD is a complex disorder, for which 13Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are the main risk 14 factors 6 . The development of infection-relevant PUD is recognised to be a multistep process, with 15 contributions from both Helicobacter pylori infection and subsequent inflammation and damage of mucosa 6 . 16Eradicating Helicobacter pylori is effective for i...

Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

“…We found a causal effect of GERD on endometriosis as well as a bidirectional causal relationship between depression and GERD. The finding for depression and GERD agrees not only with a previous observational study (Kim et al 2018) but also a recent GWAS analysis (Wu et al 2019). Hence, causality may indeed explain the comorbidity of depression with GERD.…”

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

“…This implies that the relationship between GERD and BE cannot be solely explained by a common direct effect of obesity. Formal Mendelian randomisation (MR) analyses have been attempted previously 38 ; however, interpreting the results from such studies is difficult given we have shown that there are at least two pathways leading to GERD (one acting via obesity associated SNPs, another acting via depression SNPs).…”

Mapping phenotypic and aetiological associations between ADHD and physical conditions in adulthood in Sweden: a genetically informed register study

“…When examining nervous system disorders separately, this pattern of aetiological influences was seen for sleep disorders, whereas the correlation between ADHD and migraine was almost completely explained by genetic factors. Significant phenotypic correlations were also observed between ADHD and metabolic, respiratory, and musculoskeletal disease groups (0•14-0•16); genetic factors explained 60-69% of correlations and the remainder was explained by non-shared environmental factors (figure 2; appendix pp [15][16][17].…”

“…The few available quantitative and molecular genetic studies have revealed weak-to-moderate genetic associations between ADHD and conditions such as obesity, diabetes, asthma, epilepsy, and migraines. 6 , 16 , 17 , 18 Further research, using statistically high-powered methods and a broader range of diseases across adulthood, is needed to understand the aetiological processes underlying the increased occurrence of physical conditions in people with ADHD.…”