Commun Biol. 2022 Jul 18;5(1):691. doi: 10.1038/s42003-022-03607-2.

Emmanuel O Adewuyi ^1 2, Eleanor K O'Brien ^3 4, Dale R Nyholt ⁵, Tenielle Porter ^3 4 6, Simon M Laws ^7 8 9

Author information

¹Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia. e.adewuyi@ecu.edu.au.

²Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia. e.adewuyi@ecu.edu.au.

³Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia.

⁴Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia.

⁵Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.

⁶Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA, 6102, Australia.

⁷Centre for Precision Health, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia. s.laws@ecu.edu.au.

⁸Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Perth, WA, 6027, Australia. s.laws@ecu.edu.au.

⁹Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, WA, 6102, Australia. s.laws@ecu.edu.au.

Abstract

Consistent with the concept of the gut-brain phenomenon, observational studies suggest a relationship between Alzheimer's disease (AD) and gastrointestinal tract (GIT) disorders; however, their underlying mechanisms remain unclear. Here, we analyse several genome-wide association studies (GWAS) summary statistics (N = 34,652-456,327), to assess the relationship of AD with GIT disorders. Findings reveal a positive significant genetic overlap and correlation between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis-duodenitis, irritable bowel syndrome and diverticulosis, but not inflammatory bowel disease. Cross-trait meta-analysis identifies several loci (P_{meta-analysis} < 5 × 10^-8) shared by AD and GIT disorders (GERD and PUD) including PDE4B, BRINP3, ATG16L1, SEMA3F, HLA-DRA, SCARA3, MTSS2, PHB, and TOMM40. Colocalization and gene-based analyses reinforce these loci. Pathway-based analyses demonstrate significant enrichment of lipid metabolism, autoimmunity, lipase inhibitors, PD-1 signalling, and statin mechanisms, among others, for AD and GIT traits. Our findings provide genetic insights into the gut-brain relationship, implicating shared but non-causal genetic susceptibility of GIT disorders with AD's risk. Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity.