Genetic variability associated with oligoadenylate synthetase 1, OAS1, in myeloid cells increases the risk of Alzheimer's disease and severe COVID-19

Introduction: GWAS of late-onset AD risk have highlighted the importance of gene variants expressed by the innate immune system. Recently we and others have shown genes that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. Identifying this transcriptional network allowed us to predict new risk genes for AD, including interferon-responsive oligoadenylate synthetase 1 (OAS1). However, the function of OAS1 within microglia and its genetic pathway were not known. Methods: Genotyping of SNP rs1131454 in control and AD human samples. Weighted gene co-expression network analysis of single-cell RNA-seq data from microglia of C57BL/6J and APP(NL-G-F) knock-in mice. Human microglial-like cells derived from iPSC (h-iPSC-Mg), were transfected with siRNA to knockdown OAS1 expression, and microglial status was assessed with quantitative RT-PCR. Results and Conclusions: We show SNP rs1131454 within OAS1 is associated with AD when we genotype 1314 people with AD and 1235 controls. The rs1131454 allele associated with increased risk for AD acts an eQTL and results in altered expression of the OAS1 gene in innate immune cells. Moreover, we see that SNP rs1131454 shows significant linkage disequilibrium with SNPs recently identified to be associated with critical illness with COVID-19. By analysing single-cell RNA-seq data from isolated microglia in C57BL/6J and APP(NL-G-F) knock-in mice we identify a genetic network that is significantly upregulated with age, and with amyloid plaques, and contains the mouse orthologue Oas1a, suggesting an age-dependent function in the innate immune system. H-iPSC-Mg with knockdown of OAS1 expression and stimulation with interferon-gamma show an exaggerated pro-inflammatory response. Our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19, and that OAS1 coordinates the pro-inflammatory output of innate immune cells in response to elevated interferon levels. Understanding the mechanisms underlying this ageing-dependent genetic network containing OAS1 may aid development of treatments that benefit people with both AD and COVID-19, and may also allow us to develop biomarkers to track disease progression.