Uncovering cell-type-specific immunomodulatory variants and molecular phenotypes in COVID-19 using structurally resolved protein networks.

Immunomodulatory variants that lead to the loss or gain of specific protein interactions often manifest only as organismal phenotypes in infectious disease. Here, we propose a network-based approach to integrate genetic variation with a structurally resolved human protein interactome network to prioritize immunomodulatory variants in COVID-19. We find that, in addition to variants that pass genome-wide significance thresholds, variants at the interface of specific protein-protein interactions, even though they do not meet genome-wide thresholds, are equally immunomodulatory. The integration of these variants with single-cell epigenomic and transcriptomic data prioritizes myeloid and T cell subsets as the most affected by these variants across both the peripheral blood and the lung compartments. Of particular interest is a common coding variant that disrupts the OAS1-PRMT6 interaction and affects downstream interferon signaling. Critically, our framework is generalizable across infectious disease contexts and can be used to implicate immunomodulatory variants that do not meet genome-wide significance thresholds. [Display omitted] • Generalizable framework to identify cell-type-specific immunomodulatory variants • Identified key variants that do not pass GWAS thresholds at protein interaction interfaces • Uncovered key cellular contexts where prioritized variants have an impact • Identification and functional validation of a key immunomodulatory variant in COVID-19 Chhibbar et al. describe a framework for uncovering cell-type-specific immunomodulatory variants in COVID-19. Although most of these variants do not meet genome-wide significance thresholds, they have key molecular phenotypes by virtue of their location at protein interaction interfaces. [ABSTRACT FROM AUTHOR]