Shared Genes Identified in Alzheimer Disease and Gastrointestinal Tract Disorders

The "gut-brain axis" may play an influential role in the development of neurodegenerative diseases.

Observational studies have suggested a relationship between Alzheimer disease (AD) and gastrointestinal (GI) tract disorders, which is consistent with the concept of the gut-brain phenomenon, according to study findings published in Communications Biology.

The underlying biological mechanisms regarding the shared genetic architecture between patients with AD and those with GI tract disorders remain unclear. This has prompted researchers to analyze the results of several genome-wide association studies (GWAS). Available evidence has implied that some form of association or comorbidity exists between AD and GI tract disorders, but it is uncertain whether GI tract characteristics are risks for AD or AD characteristics are risks for GI tract disorders.

For the study, well-powered GWAS summary data were analyzed to evaluate comprehensively the potential causal association and genetic relationship between AD and GI tract disorders. A positive significant genetic overlap/correlation from large-scale GWAS has been demonstrated between AD and gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), PGM (a potential proxy for PUD or GERD), irritable bowel syndrome (IBS), gastritis-duodenitis, and diverticular disease, but not between AD and inflammatory bowel disease. To date, however, no study has leveraged the potential pleiotropy between AD and GI tract disorders as a basis for their shared genes, single nucleotide polymorphisms (SNPs), and/or susceptibility loci. 

The summary statistics from the GWAS analyzed ranged from a low sample size of 34,652 participants to a high sample size of 456,327 participants. The researchers conducted 3 broad levels of analyses: (1) SNP-level; (2) gene-level; and (3) pathway-based analyses. 

Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity.

To begin, they utilized the linkage disequilibrium score regression (LDSC) to estimate the genetic link between AD and GI tract traits, as well as the SNP effect concordance analysis (SECA) method for concordance in SNP risk effect assessment. Additionally, they performed GWAS meta-analyses, in an effort to identify SNPs and susceptibility loci shared by AD and GI tract disorders. They also used Mendelian randomization (MR) and latent causal variable (LCV) methods to evaluate potential and partial causal associations between AD and GI tract disorders. Lastly, they carried out gene and pathway-based analyses to identify shared genes that achieve genome-wide significance and biological pathways for AD and GI tract disorders. 

Per cross-trait meta-analysis, several loci (Pmeta-analysis <5 x 10–8) shared by AD and GI tract disorders (ie, GERD and PUD) were identified, including PDE4BBRINP3ATG16L1SEMA3FHLA-DRASCARA3MTSS2PHB, and TOMM40. Reinforcement of these loci was confirmed by gene-based analyses and colocalization. Based on pathway-based analyses, significant enrichment of lipid metabolism, autoimmunity, lipase inhibitors, protein cell death protein 1 (PD-1) signaling, and statin mechanisms for AD and GI tract disorders was demonstrated.

Among the study limitations is the fact that the GWAS for AD combined clinically diagnosed of AD with proxies (AD-by-proxy — ie, individuals whose parents had been diagnosed with AD). Further, since the analyses were restricted mainly to participants of European ancestry, the study findings may not be generalizable to those of other ancestries.

The researchers concluded that the findings from their analyses offer insight into the gut-brain relationship, implicating a shared, but noncausal susceptibility, of GI tract disorders with the risk for AD. “Genes and biological pathways identified are potential targets for further investigation in AD, GIT disorders, and their comorbidity,” the researchers concluded.

Disclosure: None of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies.  

References:

Adewuyi EO, O’Brien EK, Nyholt DR, Porter T, Laws SM. A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disordersCommun Biol. Published online July 18, 2022. doi:10.1038/s42003-022-03607-2