Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders

Abstract Observational studies suggest links between diabetes and gastrointestinal (GI) traits; however, the question of their underlying biological mechanisms and whether the observed relationship reflects shared genetic aetiology remains unresolved. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and common GI disorders, leveraging several large-scale genome-wide association studies (GWAS) summary statistics. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). Also, we identify several positive local genetic correlations (negative for T2D – IBD) contributing disproportionately to T2D's relationship with GI disorders. Multivariable Mendelian randomisation analyses suggest causal effects of genetic liability to T2D on PUD and gastritis-duodenitis, and a bidirectional causal association with GERD. Gene-based association analysis reveals gene-level genetic overlap between T2D and GI disorders, identifying several shared genes reaching genome-wide significance (Fisher’s combined P value [ FCP gene ] < 2.62 × 10 − 6 ). Pathway-based functional enrichment analysis implicates leptin (T2D – IBD), thyroid, interferon, and notch signalling (T2D – IBS), QT interval anomaly and abnormal circulating calcium (T2D – PUD), viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. Current findings provide evidence for a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared genetically controlled biological pathways, highlight putative causality for certain T2D – GI disorders pairs, and identify important avenues for further exploration.