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

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  • Diversity in the human genome is one factor that confers resistance and susceptibility to infectious diseases. This is observed most dramatically during pandemics, where individuals exhibit large differences in risk and clinical outcomes against a pathogen infecting large portions of the world’s populations. Here, we developed scHi-HOST (single cell High-throughput Human in vitrO Susceptibility Testing), a method for rapidly identifying genetic variants that confer resistance and susceptibility to pathogens. scHi-HOST leverages scRNA-seq (single-cell RNA-sequencing) to simultaneously assign genetic identity to individual cells in mixed infections of cell lines of European, African, and Asian origin, reveal associated genetic variants for viral entry and replication, and identify expression quantitative trait loci (eQTL). Applying scHi-HOST to influenza A virus (IAV), we identified eQTL at baseline and in genes that are induced by IAV infection. Integration of scHi-HOST with a human IAV challenge study (Prometheus) revealed that a missense variant in ERAP1 (Endoplasmic reticulum aminopeptidase 1; rs27895) was associated with flu burden in cells and in human volunteers. Functional studies using RNA interference and overexpression of alternative alleles revealed that ERAP1 is exploited by IAV to promote infection. Specifically, the nonsynonymous substitution, which results in a glycine to aspartate substitution at ERAP1 residue 348, would disrupt the substrate binding pocket of ERAP1 likely resulting in a significant altered preference for substrates, poorer catalytic efficiency, or both. Finally, rs27895 exhibits substantial population differentiation, with the higher frequency of the minor T allele in two African populations likely contributing to the greater permissivity of cells from these populations to IAV infection. The synthesis of scHi-HOST with human challenge studies is a broadly applicable method that facilitates identification of common human genetic differences that confer resistance and susceptibility to pathogens. ... [Read More]

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16 files (1.34 GB)
Data Citation
  • Ko, D., Wang, L., & Schott, B. (2022). Data from: Single-cell genome-wide association reveals a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus. Duke Research Data Repository. https://doi.org/10.7924/r4g163n0s
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  • 10.7924/r4g163n0s
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  • ark:/87924/r4g163n0s
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  • Data from: Single-cell genome-wide association reveals a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus
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Thumbnail Title Date Uploaded Actions
file details SchottWangKo_DATASET_Readme.txt 2022-01-27 Public Download
file details scHH_IAV_SexGeno2PCsGexLibSize_RASQUAL_eQTLs_qval0.05.csv.gz 2022-01-27 Public Download
file details scHH_Uninfected_SexGeno2PCsGexLibSize_RASQUAL_eQTLs_qval0.05.csv.gz 2022-01-27 Public Download
file details scHH_MeanViralReads_AllCells_EMMAX_gwasumstat.txt.gz 2022-01-27 Public Download
file details IAV_SeuratMetadata.csv 2022-02-02 Public Download
file details PR8ViralBurden_scHH_LGC.csv 2022-02-02 Public Download
file details scHH_combined_PseudoBulkRNAseq_NormalizedCountMatrix.csv 2022-02-02 Public Download
file details scHH_CombinedPhenotype.csv 2022-02-02 Public Download
file details scHH_LGC_PseudoBulkRNAseq_NormalizedCountMatrix.csv 2022-02-02 Public Download
file details Uninfected_SeuratMetadata.csv 2022-02-02 Public Download

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