Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer’s disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.

中文翻译：

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通过 OAS1 基因在阿尔茨海默氏病风险与严重 COVID-19 结果之间建立遗传联系

最近，我们报道了寡腺苷酸合成酶 1 (OAS1) 通过其在小胶质细胞表达的转录网络中的富集而导致阿尔茨海默病的风险。然而，OAS1 在小胶质细胞中的功能尚不清楚。使用来自 1313 名散发性阿尔茨海默病患者和 1234 名对照个体的基因分型，我们确认 OAS1 变体 rs1131454 与阿尔茨海默病风险增加有关。相同的 OAS1 基因座最近与严重的冠状病毒病 2019 (COVID-19) 结果有关，将这两种疾病的风险联系起来。单核苷酸多态性 rs1131454(A) 和 rs4766676(T) 与阿尔茨海默病相关，rs10735079(A) 和 rs6489867(T) 与严重的 COVID-19 相关，其中风险等位基因与 OAS1 表达降低有关。通过分析来自阿尔茨海默病和 COVID-19 患者的骨髓细胞的单细胞 RNA 测序数据，我们确定了包含干扰素 (IFN) 反应基因的共表达网络，包括 OAS1，这些基因随着年龄和这两种疾病而显着上调。在 OAS1 表达降低的人诱导多能干细胞来源的小胶质细胞中，我们显示在 IFN-γ 刺激下 TNF-α 的过度产生，表明需要 OAS1 来限制骨髓细胞的促炎反应。总的来说，我们的数据支持阿尔茨海默病的遗传风险与以 OAS1 为中心的 COVID-19 对危重疾病的易感性之间存在联系，这一发现对阿尔茨海默病和 COVID-19 的未来治疗以及跟踪疾病进展的生物标志物的开发具有潜在影响.