Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

Щербак, С. Г.; Changalidis, Anton I; Barbitoff, Yury A.; Anisenkova, A.Yu.; Mosenko, S. V.; Asaulenko, Zakhar P.; Tsay, Victoria V.; Polev, Dmitry E.; Kalinin, Roman S.; Eismont, Yuri A.; Glotov, Andrey S.; Garbuzov, Evgeny Y.; Chernov, Alexander N.; Клиценко, О. А.; Ushakov, Mikhail O; Shikov, Anton E.; Urazov, Stanislav P.; Baranov, Vladislav S; Glotov, Oleg S.

doi:10.3390/genes13030534

Cited by 7 publications

(5 citation statements)

References 46 publications

(55 reference statements)

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“…Analysis of rare HI variants in different gene sets showed the maximum burden effect size for PID genes followed by essential genes; among gene sets associated with diseases of various body systems, the highest enrichment levels were obtained for the immune and respiratory disease genes, while the least pronounced association signal was recorded for genes associated with neoplasia. Because major studies of host genetics in COVID-19 patients have focused on individual SNPs, genes, and pathway-level associations, which are limited to a relatively small number of predominantly “core” genes ( Zhang et al, 2020 ; Kosmicki et al, 2021a ; López-Rodríguez et al, 2022 ; Shcherbak et al, 2022 ) our study can be viewed as the first experimental work within the omnigenic model of polygenic heritability ( Mathieson, 2021 ) in severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 severity: does the genetic landscape of rare variants matter?

et al. 2023

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Rare variants affecting host defense against pathogens may be involved in COVID-19 severity, but most rare variants are not expected to have a major impact on the course of COVID-19. We hypothesized that the accumulation of weak effects of many rare functional variants throughout the exome may contribute to the overall risk in patients with severe disease. This assumption is consistent with the omnigenic model of the relationship between genetic and phenotypic variation in complex traits, according to which association signals tend to spread across most of the genome through gene regulatory networks from genes outside the major pathways to disease-related genes. We performed whole-exome sequencing and compared the burden of rare variants in 57 patients with severe and 29 patients with mild/moderate COVID-19. At the whole-exome level, we observed an excess of rare, predominantly high-impact (HI) variants in the group with severe COVID-19. Restriction to genes intolerant to HI or damaging missense variants increased enrichment for these classes of variants. Among various sets of genes, an increased signal of rare HI variants was demonstrated predominantly for primary immunodeficiency genes and the entire set of genes associated with immune diseases, as well as for genes associated with respiratory diseases. We advocate taking the ideas of the omnigenic model into account in COVID-19 studies.

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Section: Discussionmentioning

confidence: 99%

COVID-19 severity: does the genetic landscape of rare variants matter?

et al. 2023

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“…The set of controls was selected from the RUSeq database (Barbitoff et al., 2021 ), and mainly comprised samples used in a recent association analysis for COVID‐19 (Shcherbak et al., 2022 ). The inclusion of controls was based on clear indication of health status, same sequencing technology and library preparation method, age (only donors aged 70 years and younger were included) (mean age = 42.4 years, 54% female, 46% male).…”

Section: Methodsmentioning

confidence: 99%

Exome sequencing in extreme altitude mountaineers identifies pathogenic variants in RTEL1 and COL6A1 previously associated with respiratory failure

Maksiutenko,

Merkureva,

Barbitoff

et al. 2024

Physiological Reports

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Adaptation of humans to challenging environmental conditions, such as extreme temperature, malnutrition, or hypoxia, is an interesting phenomenon for both basic and applied research. Identification of the genetic factors contributing to human adaptation to these conditions enhances our understanding of the underlying molecular and physiological mechanisms. In our study, we analyzed the exomes of 22 high altitude mountaineers to uncover genetic variants contributing to hypoxic adaptation. To our surprise, we identified two putative loss‐of‐function variants, rs1385101139 in RTEL1 and rs1002726737 in COL6A1 in two extremely high altitude (personal record of more than 8500 m) professional climbers. Both variants can be interpreted as pathogenic according to medical geneticists' guidelines, and are linked to inherited conditions involving respiratory failure (late‐onset pulmonary fibrosis and severe Ullrich muscular dystrophy for rs1385101139 and rs1002726737, respectively). Our results suggest that a loss of gene function may act as an important factor of human adaptation, which is corroborated by previous reports in other human subjects.

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“…Given multiple previous reports related to the impact of pathogenic genetic variants on the severity and outcome of COVID-19 30 , we set off to test such effect using our cohort of 444 patients with varying degree of severity of the disease and clinical outcomes.…”

Section: Identi Cation Of Pathogenic Variants In Covid-19 Patientsmentioning

confidence: 99%

Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

Kamenarova,

Kachakova-Yordanova,

Baymakova

et al. 2024

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

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Identification of Genetic Risk Factors of Severe COVID-19 Using Extensive Phenotypic Data: A Proof-of-Concept Study in a Cohort of Russian Patients

Cited by 7 publications

References 46 publications

COVID-19 severity: does the genetic landscape of rare variants matter?

COVID-19 severity: does the genetic landscape of rare variants matter?

Exome sequencing in extreme altitude mountaineers identifies pathogenic variants in RTEL1 and COL6A1 previously associated with respiratory failure

Rare host variants in ciliary expressed genes contribute to COVID-19 severity in Bulgarian patients

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