Basic Science and Pathogenesis.

Background: An increasing body of evidence has suggested that the pathogenesis of Alzheimer's disease (AD) is not confined to the neurons but instead that neuroinflammation plays a significant role in the disease, with an interplay between the brain and the immune system. So far, their shared genetic components have not been systematically studied.

Method: We investigated the shared genetic architecture between AD and a plethora of immune-mediated diseases using the genome-wide association studies (GWAS) summary statistics data: allergic rhinitis, asthma, atopic dermatitis, celiac disease, Crohn's disease, hypothyroidism, primary sclerosing cholangitis, RA, systemic lupus erythematosus, ulcerative colitis, and vitiligo. We developed a pipeline for global and local genetic correlation analysis between diseases and quantifying the shared loci among diseases using MiXeR. We used the conditional/comjunctional FDR to identify the shared loci and, finally, performed bi-directional MR to assess the causal relationship between AD and the 11 immune-mediated diseases.

Result: Our results unveiled a significant genetic overlap between AD and 11 individual immune-mediated diseases despite negligible genetic correlations, suggesting a complex shared genetic architecture distributed across the genome. With conjFDR <0.05, we identified 76 shared genomic loci. After excluding the 6 loci jointly associated with more than one pair of diseases, we had 70 unique shared genomic loci between AD and immune-mediated diseases. Among them, 38 loci were novel for AD only, 25 were novel for immune-mediated diseases only, and 17 were novel to both AD and immune-mediated diseases. The shared loci between AD and immune-mediated diseases implicated several genes, including GRAMD1B, FUT2, ADAMTS4, HBEGF, WNT3, TSPAN14, DHODH, ABCB9 and TNIP1, all of which are protein-coding genes and thus potential drug targets. Enrichment analysis of these shared genes revealed pathways related to the immune system and cell adhesion. Finally, in silico single-cell analyses showed enrichment of immune and brain cells, including neurons and microglia.

Conclusion: Our results suggest a genetic relationship between AD and the 11 immune-mediated diseases, pinpointing the existence of a shared however non-causal genetic basis. These identified protein-coding genes have the potential to serve as a novel path to therapeutic interventions for both AD and immune-mediated diseases and their comorbidities.