COVID-19 host genetics and post-infection outcomes

Using collaborative human genetics to study susceptibility, severity, and long-term outcomes of COVID-19

The severity of an infectious disease reflects not only the pathogen and a person’s exposures, but also variation in the host genome. During the COVID-19 pandemic, I contributed to the COVID-19 Host Genetics Initiative, a global open-science collaboration created to identify genetic factors that influence susceptibility to SARS-CoV-2 infection and the severity of COVID-19. I led the Initiative’s Mendelian randomization working group, which used genetic data to distinguish risk factors that may contribute causally to severe disease from factors that are merely correlated with it.

In the Initiative’s first major analysis, we combined data from nearly 50,000 people with COVID-19 across 46 studies in 19 countries. We identified 13 regions of the genome associated with infection or severe disease, including regions involved in lung biology, inflammation, and immune responses. Mendelian randomization supported causal roles for smoking and higher body mass index in severe COVID-19. As the collaboration expanded to more than 219,000 cases and over three million controls, we identified 51 associated regions and mapped them to three major biological processes: viral entry into cells, defense within airway mucus, and the type I interferon immune response. These analyses also strengthened evidence for smoking and impaired kidney function as contributors to severe outcomes.

I later contributed to the first large genome-wide study of long COVID. Across international discovery and replication cohorts, we identified variation near FOXP4 that increased long-COVID risk independently of its known association with acute COVID-19 severity. Because FOXP4 has an important role in lung function, this result connected persistent post-infection symptoms to pulmonary biology while also showing that long COVID has genetic influences distinct from those governing acute infection. Together, this work demonstrates how rapid, collaborative genetic research can reveal disease mechanisms, evaluate modifiable risk factors, and build a foundation for studying both acute and long-term consequences of an emerging infection.

Selected publications