SynthesisInfluenza and other respiratory viruses2026
Genome-Wide Association Studies of Hospitalized Influenza Identify Four Risk Loci and Reveal Shared and Unique Genetic Factors Compared With COVID-19.
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Abstract
backgroundInfluenza remains a significant global health burden, potentially leading to hospitalization and mortality. Although previous studies have explored genetic susceptibility to influenza infection, the genetic basis of influenza hospitalization and its relationship with respiratory diseases like COVID-19 remain poorly understood.
methodsWe performed a binary GWAS of hospitalized influenza using UK Biobank data (UKBB; 1037 cases/404,108 controls) and then meta-analyzed results with the FinnGen GWAS, yielding 11,171 cases and 782,400 controls. A time-to-event GWAS in UKBB was also performed to identify genetic factors underlying the timing (age) of first influenza hospitalization. p-values from both analyses were integrated by the harmonic mean p-value (HMP) method to enhance association detection. Further differentiation and colocalization analyses with COVID-19 investigated their distinct and shared genetic features. An integrative framework combining functional annotations, multi-omics analyses, and phenome-wide scans prioritized key risk and differential genes.
resultsThe binary GWAS meta-analysis identified three loci (ST6GAL1, AASDHPPT, SPATS2L) associated with hospitalization risk. The time-to-event GWAS recognized UGT2B4 as linked to hospitalization timing. HMP analysis, which combines evidence across the binary and time-to-event analyses, identified ST6GAL1 (p = 3 × 10
conclusionsThis study uncovers the genetic architectures of hospitalized influenza. It also highlights genetic differences and similarities with COVID-19, providing hypothesis-generating insights that may inform future functional and therapeutic research.
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