Genetic Variants Specific to Critical COVID-19: Insights From Genome-Wide Association Studies and Structural Analysis
Hongwei Chen1,2, Zan Li1,2, Xue Han3
1Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, P. R. China.
Journal of Medical Virology
|November 21, 2025
Summary
Genetic variants influence COVID-19 severity. Specific missense variants in genes like FUT2 increase critical illness risk, while others, such as soluble ICAM5, offer protection, revealing key pathways in disease progression.
Area of Science:
- Genetics
- Immunology
- Computational Biology
Background:
- Genome-wide association studies (GWAS) have identified genetic factors influencing COVID-19 susceptibility and severity.
- Identifying specific variants driving progression from hospitalization to critical illness remains a challenge.
Purpose of the Study:
- To pinpoint genetic variants associated with the progression of COVID-19 from hospitalization to critical illness.
- To investigate the functional impact of these severity-specific variants on protein function and disease pathways.
Main Methods:
- Identified 394 symptom-differentiating single nucleotide polymorphisms (sdSNPs) by comparing GWAS data between critical and hospitalized COVID-19 cases.
- Performed structural modeling to assess the impact of missense variants on protein stability.
- Utilized Mendelian randomization (MR) analyses, including SMR and cis-pQTL, to establish causal relationships between genetic variants, gene expression, protein levels, and COVID-19 severity.
Main Results:
- Thirteen missense variants were identified as potential drivers of phenotype conversion.
- Structural modeling predicted functional consequences for eight proteins, including FUT2, ICAM5, and MICB, impacting immune signaling.
- MR analyses showed higher FUT2 expression is linked to increased critical COVID-19 risk, while higher soluble ICAM5 (sICAM5) levels are protective, with stronger effects in critical cases.
Conclusions:
- Identified a specific set of genetic variants associated with COVID-19 severity.
- Provided mechanistic insights into how missense mutations influence disease progression via structural and regulatory effects.
- Highlighted the roles of FUT2 and ICAM5 in modulating COVID-19 critical illness risk and outcomes.
Keywords:
COVID‐19 severityMendelian randomizationmissense variantsprotein structure predictionsymptom‐differentiating SNPsMore Related Videos
04:41Mapping Alzheimer's Disease Variants to Their Target Genes Using Computational Analysis of Chromatin Configuration
Published on: January 9, 2020
19.3K
07:15Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
11.3K
Related Concept Videos
01:05Single Nucleotide Polymorphisms-SNPs
17.9K
A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
17.9K
01:11Genome-wide Association Studies-GWAS
15.2K
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
GWAS does not require the identification of the target gene involved in...
15.2K
02:26Comparing Copy Number Variations and SNPs
18.5K
Sequencing of the human genome has opened up several best-kept secrets of the genome. Scientists have identified thousands of genome variations that exist within a population. These variations can be a single nucleotide or a larger chromosomal variation.
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
18.5K
02:28Leaky Scanning
5.6K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.6K
00:36Viral Mutations
39.6K
A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
39.6K
02:30Histone Variants at the Centromere
4.9K
Histone variants are the histone proteins with structural and sequence variations. These variants may be regarded as “mutant” forms that replace their canonical histone counterparts in the nucleosomes. Specific post-translational modifications on the histone variants enable further chromatin complexity and regulate tissue-specific gene expression. The most common histone variants are from histone H2A, H2B, and linker histone H1 families. However, several variants of histone H3...
4.9K