Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection

Dobrindt, Kristina; Hoagland, Daisy A.; Seah, Carina; Kassim, Bibi; O’Shea, Callan P.; Murphy, Aleta; Iskhakova, Marina; Fernando, Michael B.; Powell, Samuel K.; Deans, P. J. Michael; Javidfar, Ben; Peter, Cyril; Møller, Rasmus; Uhl, Skyler A.; Garcia, Meilin Fernandez; Kimura, Masaki; Iwasawa, Kentaro; Crary, John F.; Kotton, Darrell N.; Takebe, Takanori; Huckins, Laura M.; tenOever, Benjamin R.; Akbarian, Schahram; Brennand, Kristen J.

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population, and located in the 3’UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs.