CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
Eur J Epidemiol. 2023 Aug;38(8):883-889. doi: 10.1007/s10654-023-01020-5. Epub 2023 Jun 26.
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to life-threatening respiratory symptoms. Understanding the genetic basis of the prognosis of COVID-19 is important for risk profiling of potentially severe symptoms. Here, we conducted a genome-wide epistasis study of COVID-19 severity in 2243 patients with severe symptoms and 12,612 patients with no or mild symptoms from the UK Biobank, followed by a replication study in an independent Spanish cohort (1416 cases, 4382 controls). Our study highlighted 3 interactions with genome-wide significance in the discovery phase, nominally significant in the replication phase, and enhanced significance in the meta-analysis. For example, the lead interaction was found between rs9792388 upstream of PDGFRL and rs3025892 downstream of SNAP25, where the composite genotype of rs3025892 CT and rs9792388 CA/AA showed higher risk of severe disease than any other genotypes (P = 2.77 × 10, proportion of severe cases = 0.24 ~ 0.29 vs. 0.09 ~ 0.18, genotypic OR = 1.96 ~ 2.70). This interaction was replicated in the Spanish cohort (P = 0.002, proportion of severe cases = 0.30 ~ 0.36 vs. 0.14 ~ 0.25, genotypic OR = 1.45 ~ 2.37) and showed enhanced significance in the meta-analysis (P = 4.97 × 10). Notably, these interactions indicated a possible molecular mechanism by which SARS-CoV-2 affects the nervous system. The first exhaustive genome-wide screening for epistasis improved our understanding of genetic basis underlying the severity of COVID-19.
新型冠状病毒病 2019（COVID-19）由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起，可能导致危及生命的呼吸道症状。了解 COVID-19 预后的遗传基础对于潜在严重症状的风险分析很重要。在这里，我们对英国生物银行中 2243 名严重症状患者和 12612 名无或轻度症状患者的 COVID-19 严重程度进行了全基因组上位性研究，随后在独立的西班牙队列中进行了复制研究（1416 例，4382 例对照）。我们的研究在发现阶段强调了 3 个具有全基因组意义的相互作用，在复制阶段具有名义意义，在荟萃分析中具有增强的意义。例如，在 PDGFRL 上游的 rs9792388 和 SNAP25 下游的 rs3025892 之间发现了主要相互作用，rs3025892 CT 和 rs9792388 CA/AA 的复合基因型比任何其他基因型显示出更高的严重疾病风险（P=2.77×10，严重病例比例=0.240.29 vs. 0.090.18，基因型 OR=1.962.70）。这种相互作用在西班牙队列中得到了复制（P=0.002，严重病例比例=0.300.36 vs. 0.140.25，基因型 OR=1.452.37），并在荟萃分析中显示出增强的意义（P=4.97×10）。值得注意的是，这些相互作用表明了 SARS-CoV-2 影响神经系统的可能分子机制。首次全基因组上位性筛选提高了我们对 COVID-19 严重程度遗传基础的理解。
