Table4_Prioritisation of Candidate Genes Underpinning COVID-19 Host Genetic Traits Based on High-Resolution 3D Chromosomal Topology.XLSX

Genetic variants showing associations with specific biological traits and diseases detected by genome-wide association studies (GWAS) commonly map to non-coding DNA regulatory regions. Many of these regions are located considerable distances away from the genes they regulate and come into their proximity through 3D chromosomal interactions. We previously developed COGS, a statistical pipeline for linking GWAS variants with their putative target genes based on 3D chromosomal interaction data arising from high-resolution assays such as Promoter Capture Hi-C (PCHi-C). Here, we applied COGS to COVID-19 Host Genetic Consortium (HGI) GWAS meta-analysis data on COVID-19 susceptibility and severity using our previously generated PCHi-C results in 17 human primary cell types and SARS-CoV-2-infected lung carcinoma cells. We prioritise 251 genes putatively associated with these traits, including 16 out of 47 genes highlighted by the GWAS meta-analysis authors. The prioritised genes are expressed in a broad array of tissues, including, but not limited to, blood and brain cells, and are enriched for genes involved in the inflammatory response to viral infection. Our prioritised genes and pathways, in conjunction with results from other prioritisation approaches and targeted validation experiments, will aid in the understanding of COVID-19 pathology, paving the way for novel treatments.

通过全基因组关联分析（Genome-Wide Association Studies, GWAS）检测到的与特定生物学性状及疾病相关的遗传变异，通常定位于非编码DNA调控区域。此类区域大多距离其所调控的基因较远，需通过三维染色体相互作用才能与靶基因形成空间邻近关系。我们此前开发了COGS——一款基于高分辨率实验（如启动子捕获Hi-C（Promoter Capture Hi-C, PCHi-C））产生的三维染色体相互作用数据，将GWAS变异与其推定靶基因进行关联的统计分析流程。本研究将COGS应用于新冠宿主遗传学联盟（COVID-19 Host Genetic Consortium, HGI）针对新冠易感性与重症程度的GWAS荟萃分析数据，所用的PCHi-C数据来自我们此前在17种人类原代细胞类型以及严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染的肺癌细胞中获得的实验结果。我们最终筛选出251个与上述性状推定相关的基因，其中包含GWAS荟萃分析作者所标注的47个基因中的16个。这些优先筛选得到的基因在多种组织中广泛表达，涵盖但不限于血液与脑细胞，且在针对病毒感染的炎症反应相关基因中显著富集。我们筛选得到的基因及通路，结合其他优先级筛选方法与靶向验证实验的结果，将有助于解析新冠的病理机制，为新型治疗手段的开发铺平道路。