Feng Yaning, Wong Kenneth Chi-Yin, Tsui Wai Kai, Zhang Ruoyu, Xiang Yong, So Hon-Cheong
School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou 310053, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Int J Mol Sci. 2025 Jul 4;26(13):6441. doi: 10.3390/ijms26136441.
The coronavirus disease 2019 (COVID-19) pandemic has led to substantial health and financial burdens worldwide, and vaccines provide hope for reducing the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWASs) may identify potential genetic factors involved in the development of COVID-19 breakthrough infections (BIs); however, very few or no GWASs have been conducted for COVID-19 BI thus far. We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BIs in a European population via the UK Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BIs and hospitalized infections. The polygenic risk score (PRS) and Hoeffding's test were performed to reveal the genetic relationships between BIs and other medical conditions. Two independent loci (LD-clumped at r = 0.01) reached genome-wide significance ( < 5 × 10), including rs36170929, which mapped to /, and rs28645263, which mapped to . A pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. The PRS analyses revealed significant genetic overlap between COVID-19 BIs and heart failure and between HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BIs and asthma, lung abnormalities, schizophrenia, and type 1 diabetes on the basis of Hoeffding's test. This GWAS revealed two significant loci that may be associated with COVID-19 BIs and a number of genes and pathways that may be involved in BIs. Genetic overlap with other diseases was identified. Further studies are warranted to replicate these findings and elucidate the mechanisms involved.
2019年冠状病毒病（COVID-19）大流行给全球带来了巨大的健康和经济负担，而疫苗为减轻这一流行病的负担带来了希望。然而，接种疫苗的人仍有感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的风险。全基因组关联研究（GWAS）可能会识别出与COVID-19突破性感染（BI）发生相关的潜在遗传因素；然而，迄今为止，针对COVID-19 BI进行的GWAS非常少或几乎没有。我们通过英国生物银行（UKBB）对欧洲人群中的COVID-19 BI进行了GWAS和详细的生物信息学分析。我们在不同层面进行了一系列分析，包括基于单核苷酸多态性（SNP）、基于基因、通路和全转录组关联分析，以研究与COVID-19 BI和住院感染相关的遗传因素。进行了多基因风险评分（PRS）和霍夫丁检验，以揭示BI与其他疾病状况之间的遗传关系。两个独立的基因座（在r = 0.01时进行连锁不平衡聚类）达到全基因组显著性水平（< 5×10），包括映射到/的rs36170929和映射到的rs28645263。通路富集分析突出了病毒性心肌炎、Rho选择性鸟嘌呤交换因子AKAP13信号传导和脂质代谢等通路。PRS分析揭示了COVID-19 BI与心力衰竭之间以及糖化血红蛋白（HbA1c）与1型糖尿病之间存在显著的遗传重叠。基于霍夫丁检验，还观察到COVID-19 BI与哮喘、肺部异常、精神分裂症和1型糖尿病之间存在遗传依赖性。这项GWAS揭示了两个可能与COVID-19 BI相关的显著基因座以及一些可能参与BI的基因和通路。确定了与其他疾病的遗传重叠。有必要进行进一步研究以重复这些发现并阐明其中涉及的机制。
