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Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19

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 assu...

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Autores principales: Khadzhieva, Maryam B., Kolobkov, Dmitry S., Kashatnikova, Darya A., Gracheva, Alesya S., Redkin, Ivan V., Kuzovlev, Artem N., Salnikova, Lyubov E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526997/
https://www.ncbi.nlm.nih.gov/pubmed/37759780
http://dx.doi.org/10.3390/biom13091380
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author Khadzhieva, Maryam B.
Kolobkov, Dmitry S.
Kashatnikova, Darya A.
Gracheva, Alesya S.
Redkin, Ivan V.
Kuzovlev, Artem N.
Salnikova, Lyubov E.
author_facet Khadzhieva, Maryam B.
Kolobkov, Dmitry S.
Kashatnikova, Darya A.
Gracheva, Alesya S.
Redkin, Ivan V.
Kuzovlev, Artem N.
Salnikova, Lyubov E.
author_sort Khadzhieva, Maryam B.
collection PubMed
description 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.
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spelling pubmed-105269972023-09-28 Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19 Khadzhieva, Maryam B. Kolobkov, Dmitry S. Kashatnikova, Darya A. Gracheva, Alesya S. Redkin, Ivan V. Kuzovlev, Artem N. Salnikova, Lyubov E. Biomolecules Communication 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. MDPI 2023-09-12 /pmc/articles/PMC10526997/ /pubmed/37759780 http://dx.doi.org/10.3390/biom13091380 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Khadzhieva, Maryam B.
Kolobkov, Dmitry S.
Kashatnikova, Darya A.
Gracheva, Alesya S.
Redkin, Ivan V.
Kuzovlev, Artem N.
Salnikova, Lyubov E.
Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title_full Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title_fullStr Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title_full_unstemmed Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title_short Rare Variants in Primary Immunodeficiency Genes and Their Functional Partners in Severe COVID-19
title_sort rare variants in primary immunodeficiency genes and their functional partners in severe covid-19
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10526997/
https://www.ncbi.nlm.nih.gov/pubmed/37759780
http://dx.doi.org/10.3390/biom13091380
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