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.
Document Type
Journal Article
Date of Publication
12-1-2024
Volume
7
Issue
1
PubMed ID
38802514
Publication Title
Communications Biology
Publisher
Nature
School
Centre for Precision Health / School of Medical and Health Sciences
RAS ID
70261
Funding Information
SML received funding from the National Health and Medical Research Council Australia (APP1161706, APP1191535), while EOA was supported by the Department of Health Western Australia, Future Health Research and Innovation—WA Near-miss Awards: Emerging Leaders Program (G1006599). This activity has been supported by the Western Australian Future Health Research and Innovation Fund.
Funding received from the National Health and Medical Research Council (NHMRC)
APP1161706, APP1191535
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Content Type
Full object
Recommended Citation
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
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