Identification of host genetic variation predisposing to severe COVID-19 by genetics, transcriptomics and functional analyses

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Unraveling genetic predispositions to severe COVID-19 promises to shed light onto the heterogeneity of the immune response to SARS-CoV-2 infection and to yield opportunities to better understand and potentially alter the underlying pathophysiology. Genetic loci harboring candidate genes related to innate immune response associate with COVID-19 have been identified. However, data systematically characterizing the functional impact of such genetic variation are sparse. In search for rare variants of strong effect, the global COVID-19 Host Genetics Initiative (COVID-19 HGI; www.covid19hg.org) is now expanding into rare variant association studies (RVAS) using whole exome and whole genome sequencing (WES/WGS) of large international cohorts. However, the identification and functional validation of these variants requires complementary data and analyses. This is particularly true for regulatory variants (e.g. variants effecting splicing) whose impacts are not yet defined for COVID-19 and hard to predict from sequence alone. Here, we will (1) generate a comprehensive genomics-transcriptomics data set for a longitudinally-followed cohort of individuals with COVID-19, (2) use a novel bioinformatics algorithm to identify aberrant splicing and expression as well as underlying genetic factors contributing to severe COVID-19 and (3) employ the results from this analysis as well as already existing large-scale genetic and functional annotation data to prioritize genes and genetic variants of innate-immune response pathways for (4) functional analysis by in vitro complementation.Overall, this project will allow for focused, hypothesis-driven analyses of innate immune-response in SARS-CoV-2 infection with unbiased discovery of novel genes and variants by rare-variant association study and aberrant expression analysis. To our knowledge, aberrant expression-based gene and variant prioritization has not been applied to COVID-19 so far. Ultimately, this will lead to the identification of genetic variants with functional relevance to SARS-CoV-2 and, in particular, to a more detailed understanding of the role of innate-immune-response genes in COVID-19 pathophysiology. This fundamental understanding bears the potential to generate new models to study SARS-CoV-2 infection and to develop highly specific novel or identify repurposable drugs to treat (subgroups of) individuals with COVID-19.