Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus
Year: 2022
Type: article
Abstract: 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.
Source: Cell Genomics
Authors: Benjamin H. Schott, Liuyang Wang, Xinyu Zhu, Alfred T. Harding, Emily R. Ko, Jeffrey S. Bourgeois, Erica J. Washington, Thomas W. Burke, Jack Anderson, Emma Bergstrom, Zoe Gardener, Suzanna Paterson, Richard G. Brennan, Christopher Chiu, Micah T. McClain, Christopher W. Woods, Simon G. Gregory, Nicholas S. Heaton, Dennis C. Ko
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $8,900
Funders: Duke University, National Institute on Handicapped Research, Prometheus, National Institute for Health and Care Research, Department of Health and Social Care, Imperial College London, Imperial College Healthcare NHS Trust, National Institutes of Health, Defense Advanced Research Projects Agency, Manchester Biomedical Research Centre, NIHR Imperial Biomedical Research Centre, National Institute of Allergy and Infectious Diseases
Awards: G1037014486, Mechanisms of methylthioadenosine signaling during Salmonella infection, G2399320897, G4376777816, Human Genetic Variation Regulating Transcriptional Response and Cellular Susceptibility to Influenza, G8079563027, G9000261663, Genetic Contributors to the Impact of Sex on Heterogeneity in Flu Infection
OpenAlex ID: W4308739959