Identification of pathogenic cell types and shared genetic loci and genes for Alzheimer's disease and inflammatory bowel disease.

Background: Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, but the underlying intrinsic link between Alzheimer's disease (AD) and inflammatory bowel disease (IBD) is not adequately understood.

Methods: To identify pathogenic cell types of AD and IBD and explore their shared genetic architecture, we developed Pathogenic Cell types and shared Genetic Loci (PCGL) framework, which studied AD and IBD and its two subtypes of ulcerative colitis (UC) and Crohn's disease (CD).

Results: We found that monocytes and CD8 T cells were the enriched pathogenic cell types of AD and IBDs, respectively. By PCGL framework, there was a significant global genetic correlation between AD and each of IBD, UC, and CD. Especially, local genetic correlations between AD and IBD showed strong signals in chr6. Bidirectional two-sample MR Analyses also validated these. Cross-trait meta-analysis identified two key genetic loci rs660895 (on chr6) and rs917117 (on chr7), which have not been previously reported. Two loci are located on the genes HLA-DRB1 and JAZF1, respectively. MAGMA genome-wide gene-based analysis identified six overlapping genes including HLA-DRB1. Subsequently, for one thing, SMR analyses further validated six shared genes in specific tissues and monocytes. For another, pathway enrichment analysis revealed shared genes were enriched in several natural killer cell mediated cytotoxicity and chemokine signaling pathways.

Conclusions: PCGL not only revealed the significant genetic correlations underlying AD and IBDs but also identified enriched pathogenic cell types and new shared loci and genes. We highlighted the mediation of HLA-DRB1 effects in the comorbidity mechanisms.