Abstract

A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer's disease and gastrointestinal tract disorders

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

 

Emmanuel O Adewuyi 1 2Eleanor K O'Brien 3 4Dale R Nyholt 5Tenielle Porter 3 4 6Simon 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 (Pmeta-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.

 

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