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

Abstract

Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. 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). We identify several positive local genetic correlations (negative for T2D – IBD) contributing to T2D’s relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D – IBD), thyroid, interferon, and notch signalling (T2D – IBS), abnormal circulating calcium (T2D – PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D – GI pairs, and identify targets for further investigation.

Investigating genetic overlap between Alzheimer's disease, lipids, and coronary artery disease: a large-scale genome-wide cross trait analysis

“…A robust signal in the local univariate analysis is a prerequisite for detecting bivariate genetic correlations in LAVA [26]. From the outcomes of the univariate analysis, we selected traits for bivariate analysis at a significance level of 𝜌 < 5 x 10 -2 (to allow more bivariate analysis without the risk of false positives as recently implemented [51]).…”

“…Finally, similar to a recent study [51], we conducted pair-wise bivariate local genetic correlation analyses across the genome for AD, lipids (HDL, LDL, Triglycerides, and Total cholesterol), and seven CAD traits. Applying a Bonferroni correction for the highest number of bivariate tests performed (AD Jansen et al [27] -vs-CAD (35 bivariate tests), we considered bivariate analysis results significant at 𝜌 < 1.4 x 10 -3 (that is 0.05/35).…”