The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia.
The Laboratory of Ecological Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia.
Biomolecules. 2023 Sep 12;13(9):1380. doi: 10.3390/biom13091380.
The development of severe COVID-19, which is a complex multisystem disease, is thought to be associated with many genes whose action is modulated by numerous environmental and genetic factors. In this study, we focused on the ideas of the omnigenic model of heritability of complex traits, which assumes that a small number of core genes and a large pool of peripheral genes expressed in disease-relevant tissues contribute to the genetics of complex traits through interconnected networks. We hypothesized that primary immunodeficiency disease (PID) genes may be considered as core genes in severe COVID-19, and their functional partners (FPs) from protein-protein interaction networks may be considered as peripheral near-core genes. We used whole-exome sequencing data from patients aged ≤ 45 years with severe ( = 9) and non-severe COVID-19 ( = 11), and assessed the cumulative contribution of rare high-impact variants to disease severity. In patients with severe COVID-19, an excess of rare high-impact variants was observed at the whole-exome level, but maximal association signals were detected for PID + FP gene subsets among the genes intolerant to LoF variants, haploinsufficient and essential. Our exploratory study may serve as a model for new directions in the research of host genetics in severe COVID-19.
严重 COVID-19 是一种复杂的多系统疾病，其发展被认为与许多基因有关，这些基因的作用受到许多环境和遗传因素的调节。在这项研究中，我们专注于复杂性状遗传的全基因组模型的观点，该模型假设一小部分核心基因和大量在疾病相关组织中表达的外围基因通过相互关联的网络为复杂性状的遗传学做出贡献。我们假设原发性免疫缺陷病 (PID) 基因可以被视为严重 COVID-19 的核心基因，而其来自蛋白质-蛋白质相互作用网络的功能伙伴 (FP) 可以被视为外围近核心基因。我们使用了来自年龄 ≤ 45 岁的严重 ( = 9) 和非严重 COVID-19 ( = 11) 患者的全外显子组测序数据，并评估了罕见高影响变异对疾病严重程度的累积贡献。在严重 COVID-19 患者中，在全外显子组水平上观察到罕见高影响变异的过剩，但在不耐受 LoF 变异、杂合不足和必需的 PID + FP 基因亚组中检测到最大的关联信号。我们的探索性研究可以作为严重 COVID-19 宿主遗传学研究新方向的模型。
