Genetic overlap between Alzheimer’s disease and immune-mediated diseases: an atlas of shared genetic determinants and biological convergence

• Published in: Molecular psychiatry Vol. 29; no. 8; pp. 2447 - 2458
• Main Authors: Enduru, Nitesh, Fernandes, Brisa S., Bahrami, Shahram, Dai, Yulin, Andreassen, Ole A., Zhao, Zhongming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2024; Nature Publishing Group
• Subjects: 631/208; 692/699/476; Alzheimer's disease; Behavioral Sciences; Biological Psychology; Cell adhesion; Comorbidity; Disease; Epidemiology; Genetic analysis; Genetic relationship; Genome-wide association studies; Genomes; Immune system; Immunological diseases; Medicine; Medicine & Public Health; Microglia; Neurodegenerative diseases; Neurosciences; Pharmacotherapy; Psychiatry; Therapeutic applications; Therapeutic targets
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-024-02510-y

The occurrence of immune disease comorbidities in Alzheimer’s disease (AD) has been observed in both epidemiological and molecular studies, suggesting a neuroinflammatory basis in AD. However, their shared genetic components have not been systematically studied. Here, we composed an atlas of the shared genetic associations between 11 immune-mediated diseases and AD by analyzing genome-wide association studies (GWAS) summary statistics. 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. 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. Top biological pathways enriched with these identified shared genes were related to the immune system and cell adhesion. In addition, in silico single-cell analyses showed enrichment of immune and brain cells, including neurons and microglia. In summary, 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.