Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
Maryam B. Khadzhieva,
Dmitry S. Kolobkov,
Darya A. Kashatnikova,
Alesya S. Gracheva,
Ivan V. Redkin,
Artem N. Kuzovlev,
Lyubov E. Salnikova
Affiliations
Maryam B. Khadzhieva
The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia
Dmitry S. Kolobkov
The Laboratory of Ecological Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia
Darya A. Kashatnikova
The Laboratory of Ecological Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia
Alesya S. Gracheva
The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia
Ivan V. Redkin
Competence Center for the Development of AI Technology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia
Artem N. Kuzovlev
The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia
Lyubov E. Salnikova
The Laboratory of Clinical Pathophysiology of Critical Conditions, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia
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 (n = 9) and non-severe COVID-19 (n = 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.
