Comprehensive Genome‐Wide Analysis of Shared Genetic Factors in Gastrointestinal and Neurodegenerative Diseases

BACKGROUND: This study investigates the shared genetic basis between gastrointestinal (GI) diseases and neurodegenerative diseases (ND) using genome-wide association study (GWAS) data and statistical genetic methods. METHODS: GWAS data, primarily from European populations, covered four types of GI diseases and three types of ND. Genetic correlations were assessed using Linkage Disequilibrium Score Regression (LDSC), High-Definition Likelihood (HDL), and Local Analysis of Covariant Annotation (LAVA). Pleiotropic and functional genetic overlaps were explored using the Genomic Partitioning Approach (GPA), pleiotropic analysis under the composite null hypothesis (PLACO), and Functional Mapping and Annotation of Genetic Associations (FUMA). Multi-marker analysis of genomic annotation (MAGMA) was used for biological annotation and enrichment analysis, while summary data-based Mendelian randomization (SMR) analysis linked pleiotropic genes with gene expression. Two-sample Mendelian randomization (TSMR) investigated potential causal relationships. RESULTS: Significant genetic correlations and shared genetic features were identified. The research identified 1,457 pleiotropic single nucleotide variants(SNVs) distributed across 47 chromosomal regions and 74pleiotropic genes, predominantly involved in pathways related tosignal transduction, amyloid regulation, and lipid metabolism. Nine colocalization loci (PPH4 > 0.8) were identified, while SMR analysis linked 26 pleiotropic genes to disease expression levels. Key genes, including EP300, CHRNB1, KNOP1, P2RY14, and POLR2A, were significantly associated with both disease types. Drug-gene interaction analysis highlighted 8 genes with drug targets, among which EP300, PRKCB, VKORC1, and CHRNB1 were found to anchor enriched pathways including purinergic signaling, amyloid/protein aggregation, and cholesterol/lipoprotein transport. Mendelian randomization corroborated possible causal association. CONCLUSION: This study confirms a shared genetic basis between GI and ND, emphasizing the gut-brain axis in their etiology. These findings offer clues about shared pathways, potential therapeutic targets, and future research directions.