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

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

doi:10.1016/j.xgen.2022.100207

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

Cell Genom. 2022 Nov 9;2(11):100207. doi: 10.1016/j.xgen.2022.100207.

Authors

Benjamin H Schott^{1

2

3}, Liuyang Wang^{1

3}, Xinyu Zhu¹, Alfred T Harding¹, Emily R Ko^{4

5}, Jeffrey S Bourgeois^{1

2}, Erica J Washington⁶, Thomas W Burke⁴, Jack Anderson⁴, Emma Bergstrom⁷, Zoe Gardener⁷, Suzanna Paterson⁷, Richard G Brennan⁶, Christopher Chiu⁷, Micah T McClain^{4

8

9}, Christopher W Woods^{4

8

9}, Simon G Gregory¹⁰, Nicholas S Heaton¹, Dennis C Ko^{1

2

9

11}

Affiliations

¹ Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, 0048B CARL Building Box 3053, 213 Research Drive, Durham, NC 27710, USA.
² Duke University Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
³ These authors contributed equally.
⁴ Center for Applied Genomics and Precision Medicine, Department of Medicine, Duke University, Durham, NC 27710, USA.
⁵ Hospital Medicine, Division of General Internal Medicine, Department of Medicine, Duke Regional Hospital, Durham, NC 27705, USA.
⁶ Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA.
⁷ Section of Infectious Diseases and Immunity, Imperial College London, London, W12 0NN, UK.
⁸ Durham Veterans Affairs Health Care System, Durham, NC 27705, USA.
⁹ Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.
¹⁰ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
¹¹ Lead contact.

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 20^th 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.

Abstract

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