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

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.

Fig. 1. Study design and workflow: examining shared genetic and causality of GIT disorders with the risk of Alzheimer’s disease.

GWAS genome-wide association studies, SNP single-nucleotide polymorphism, SECA SNP effect concordance analysis, LDSC linkage disequilibrium score regression, LCV latent causal variable, MAGMA multi-marker analysis of genomic annotation, MR Mendelian randomisation, MR-PRESSO Mendelian randomisation pleiotropy residual sum and outlier, KEGG Kyoto Encyclopedia of Genes and Genomes.

Fig. 2. Clusters of significantly enriched biological pathways for AD and GERD.

a KEGG: Kyoto Encyclopedia of Genes and Genomes pathways: intestinal immune network (allograft rejection, intestinal immune network for IGA production, type 1 diabetes mellitus, systemic lupus erythematous, antigen processing and presentation, graft-versus-host disease, asthma), and cholesterol metabolism (cholesterol metabolism). b Gene Ontology: Cellular Components: side membrane vesicle (lumenal side of membrane, MHC class II protein complex, integral component of lumenal side of endoplasmic reticulum [ER] membrane, clathrin-coated endocytic vesicle membrane, late endosome, ER to Golgi transport vesicle membrane, coated vesicle membrane, lumenal side of ER membrane, MHC protein complex, COPII-coated ER to Golgi transport vesicle, transport vesicle membrane, late endosome membrane), and plasma lipoprotein particle (chylomicron, very low-density lipoprotein [VLDL] particle, triglyceride-rich plasma lipoprotein particle, plasma lipoprotein particle, lipoprotein particle, LDL lipoprotein particle). c Gene Ontology: Molecular Function: peptide antigen binding (peptide binding, peptide antigen binding, MHC class II receptor activity) and lipase inhibitor activity (lipase inhibitor activity). d Gene Ontology: Biological Pathway: lipoprotein particle clearance (phospholipid efflux, VLDL particle clearance, regulation of plasma lipoprotein particle levels, plasma lipoprotein particle clearance, chylomicron remnant clearance, regulation of lipid catabolic process, regulation of VLDL particle clearance, protein-lipid complex assembly, plasma lipoprotein particle organisation, regulation of phospholipid catabolic process, VLDL particle assembly, regulation of lipid localisation, glycolipid catabolic process, triglyceride-rich lipoprotein particle clearance, high density lipoprotein particle remodelling), receptor signalling pathway (T cell receptor signalling pathway, interferon-gamma-mediated signalling pathway, antigen receptor-mediated signalling pathway), membrane adhesion cell (cell-cell adhesion via plasma membrane adhesion molecules, homophilic cell adhesion via plasma membrane adhesion molecules), and negative regulation type (negative regulation of type I interferon production). e Reactome, Wiki pathway and Transcription Factor Binding site: assembly clearance plasma (statin pathway, NR1H2 and NR1H3-mediated signalling, plasma lipoprotein assembly, remodelling, and clearance, plasma lipoprotein clearance, NR1H3 and NR1H2 regulated gene expression linked to cholesterol transport and efflux, VLDL assembly, VLDL clearance, plasma lipoprotein assembly), interferon-gamma signalling (PD-1 signalling, generation of second messenger molecules, interferon-gamma signalling phosphorylation of CD3 and TCR ZETA chains, translocation of ZAP-70 to Immunological synapse), Factor: ZNF2 motif, and ZNF582 motif. Supplementary Data 26 provides additional details about these biological pathways. AD Alzheimer’s disease, GERD gastroesophageal reflux disease.