Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, China.
Department of Neurology, Xuanwu Hospital, National Center for Neurological Disorders, Capital Medical University, Beijing, China.
CNS Neurosci Ther. 2024 Jul;30(7):e14873. doi: 10.1111/cns.14873.
Alzheimer's disease (AD) is the highest risk of COVID-19 infection, hospitalization, and mortality. However, it remains largely unclear about the link between AD and COVID-19 outcomes. ACE2 is an entry receptor for SARS-CoV-2. Circulating ACE2 is a novel biomarker of death and associated with COVID-19 outcomes.
Here, we explored the shared genetics and causal association between AD and plasma ACE2 levels using large-scale genome-wide association study, gene expression, expression quantitative trait loci, and high-throughput plasma proteomic profiling datasets.
We found a significant causal effect of genetically increased circulating ACE2 on increased risk of AD. Cross-trait association analysis identified 19 shared genetic variants, and three variants rs3104412, rs2395166, and rs3135344 at chromosome 6p21.32 were associated with COVID-19 infection, hospitalization, and severity. We mapped 19 variants to 117 genes, which were significantly upregulated in lung, spleen, and small intestine, downregulated in brain tissues, and involved in immune system, immune disease, and infectious disease pathways. The plasma proteins corresponding to LST1, AGER, TNXB, and APOC1 were predominantly associated with COVID-19 infection, ventilation, and death.
Together, our findings suggest the shared genetics and causal association between AD and plasma ACE2 levels, which may partially explain the link between AD and COVID-19.
阿尔茨海默病（AD）是感染 COVID-19、住院和死亡的最高风险。然而，AD 与 COVID-19 结局之间的联系在很大程度上仍不清楚。ACE2 是 SARS-CoV-2 的进入受体。循环 ACE2 是死亡的新型生物标志物，与 COVID-19 结局相关。
在这里，我们使用大规模全基因组关联研究、基因表达、表达数量性状位点和高通量血浆蛋白质组学分析数据集，探讨了 AD 和血浆 ACE2 水平之间的共同遗传和因果关系。
我们发现循环 ACE2 遗传增加与 AD 风险增加之间存在显著的因果关系。跨性状关联分析确定了 19 个共同的遗传变异，其中三个位于 6p21.32 染色体上的变异 rs3104412、rs2395166 和 rs3135344 与 COVID-19 感染、住院和严重程度相关。我们将 19 个变异映射到 117 个基因，这些基因在肺、脾和小肠中显著上调，在脑组织中下调，并参与免疫系统、免疫性疾病和传染病途径。与 LST1、AGER、TNXB 和 APOC1 对应的血浆蛋白主要与 COVID-19 感染、通气和死亡相关。
总之，我们的研究结果表明 AD 和血浆 ACE2 水平之间存在共同的遗传和因果关系，这可能部分解释了 AD 和 COVID-19 之间的联系。
