Genetic Variants Specific to Critical COVID‐19: Insights From Genome‐Wide Association Studies and Structural Analysis

Genome-wide association studies (GWAS) have identified numerous genetic loci associated with COVID-19 susceptibility and severity. However, it remains unclear which variants specifically contribute to the progression from hospitalization to critical illness. To address this, we identified 394 symptom-differentiating SNPs (sdSNPs) by directly comparing GWAS summary statistics between critical and hospitalized COVID-19 cases. Among these, 13 were missense variants that may trigger phenotype conversion. To investigate their functional consequences, we performed structural modeling to evaluate the impact of these variants on protein stability. Eight proteins were predicted to be affected, including FUT2, ICAM5, IFNA10, PLSCR1, IZUMO1, ICAM1, RASIP1, and MICB, suggesting potential disruptions in immune signaling and host response pathways. Furthermore, Mendelian randomization analyses provided direct causal evidence: SMR analysis based on lung eQTL data demonstrated that higher FUT2 expression was significantly associated with increased risk of critical COVID-19 (β = 0.227, p = 2.69 × 10^-3), compared to a weaker effect in hospitalized COVID-19 (β = 0.096, p = 3.97 × 10^-2). In contrast, MR analysis using cis-pQTLs revealed that higher plasma levels of soluble ICAM5 (sICAM5) exerted protective effects, with stronger estimates in critical COVID-19 (β = -0.186, p = 5.54 × 10^-7) than in hospitalized COVID-19 (β = -0.095, p = 1.69 × 10^-4). These findings identify a distinct set of severity-specific genetic variants and offer mechanistic insights into how missense mutations may influence disease progression through structural and regulatory pathways.