Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus

During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and susceptibility. We applied this method to influenza A virus (IAV), the cause of four pandemics since the start of the 20th century. scHi-HOST leverages single-cell RNA sequencing (scRNA-seq) to simultaneously assign genetic identity to cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral burden, and identify expression quantitative trait loci. Integration of scHi-HOST with human challenge and experimental validation demonstrated that a missense variant in endoplasmic reticulum aminopeptidase 1 (ERAP1; rs27895) increased IAV burden in cells and human volunteers. rs27895 exhibits population differentiation, likely contributing to greater permissivity of cells from African populations to IAV. scHi-HOST is a broadly applicable method and resource for decoding infectious-disease genetics. [Display omitted] •Multi-population single-cell GWAS connects SNPs with gene expression and IAV burden•Analysis of nonsynonymous SNPs reveals ERAP1 G346D associated with viral burden•Inhibition and overexpression of ERAP1 in A549 confirms effect on viral burden•ERAP1 G346D is also associated with symptoms and viral burden in human challenge Schott et al. developed scHi-HOST, a GWAS platform leveraging scRNA-seq to assign cell identity and detect SNPs associated with pathogen resistance and gene expression in mixed infections of lymphoblastoid cell lines. scHi-HOST revealed an SNP associated with influenza burden. This association is confirmed in cell culture and human flu challenge.