Factors influencing infection with the Omicron variant differ from those associated with earlier SARS-CoV-2 variants

An international research team, including scientists from the University of Tartu, has published a genomic study in Nature Genetics showing that the genetic risk factors associated with SARS-CoV-2 Omicron infection differ markedly from those observed for earlier variants.

Omicron emerged in late 2021 as a highly mutated form of SARS-CoV-2 and rapidly became the dominant variant globally. Since then, SARS-CoV-2 has increasingly behaved like an endemic respiratory virus, causing recurrent waves that often coincide with the season when other respiratory infections, such as influenza, spread widely.

The study analysed health and genetic data from more than 700,000 individuals from the Estonian Biobank, Denmark, Finland, and the United States. The researchers identified 13 genomic regions associated with the risk of Omicron infection. Eight of these regions had not been linked to infection risk in earlier SARS-CoV-2 variant studies, indicating that the host genetic architecture of susceptibility can shift as the virus evolves.

Laboratory and model systems suggest that, compared with earlier variants, Omicron infects lung tissue less efficiently but targets the upper respiratory tract more strongly. In line with this, genetic signals in the study implicated biological processes related to the mucosal barrier and cell-surface features that can influence viral attachment, cell entry, and immune responses. Notably, parts of the pattern overlap with genetic signals previously linked to susceptibility to influenza, suggesting that different respiratory viruses may partly rely on shared host defence barriers and entry-related mechanisms.

Overall, the findings support the idea that interactions between SARS-CoV-2 and the human host are not static. As viral variants change and population-level immune backgrounds shift, the genetic factors associated with infection risk may also change. This underscores the value of updating genetic analyses during periods dominated by new variants.

The study provides deeper insight into how viral evolution and human genetic background jointly shape infection risk and highlights biological pathways that merit further investigation. The results may help refine how researchers think about risk differences across populations and contexts, especially when new variants emerge. They also point to host mechanisms that may be relevant across multiple respiratory infections, potentially informing future prevention and therapeutic research.

Read more: https://www.nature.com/articles/s41588-025-02484-9