Author Identifier
Emmanuel O. Adewuyi
https://orcid.org/0000-0002-4533-0340
Tenielle Porter
https://orcid.org/0000-0002-7887-6622
Simon M. Laws
Document Type
Journal Article
Publication Title
Communications Biology
Volume
7
Issue
1
PubMed ID
38802514
Publisher
Nature
School
Centre for Precision Health / School of Medical and Health Sciences
RAS ID
70261
Funders
National Health and Medical Research Council Australia
Department of Health Western Australia - Future Health Research and Innovation. Emerging Leaders Program (G1006599)
Western Australian Future Health Research and Innovation Fund
Grant Number
NHMRC Numbers : APP1161706, APP1191535
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.
DOI
10.1038/s42003-024-06333-z
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Adewuyi, E. O., Porter, T., O’Brien, E. K., Olaniru, O., Verdile, G., & Laws, S. M. (2024). Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders. Communications Biology, 7(1), Article 643. https://doi.org/10.1038/s42003-024-06333-z