Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Kristina Dobrindt; Daisy A Hoagland; Carina Seah; Bibi Kassim; Callan P O'Shea; Aleta Murphy; Marina Iskhakova; Michael B Fernando; Samuel K Powell; P J Michael Deans; Ben Javidfar; Cyril Peter; Rasmus Møller; Skyler A Uhl; Meilin Fernandez Garcia; Masaki Kimura; Kentaro Iwasawa; John F Crary; Darrell N Kotton; Takanori Takebe; Laura M Huckins; Benjamin R tenOever; Schahram Akbarian; Kristen J Brennand

doi:10.1016/j.stemcr.2021.02.010

Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Stem Cell Reports. 2021 Mar 9;16(3):505-518. doi: 10.1016/j.stemcr.2021.02.010. Epub 2021 Feb 13.

Authors

Kristina Dobrindt¹, Daisy A Hoagland², Carina Seah³, Bibi Kassim⁴, Callan P O'Shea⁵, Aleta Murphy⁶, Marina Iskhakova⁴, Michael B Fernando⁶, Samuel K Powell⁶, P J Michael Deans⁷, Ben Javidfar⁴, Cyril Peter⁴, Rasmus Møller², Skyler A Uhl², Meilin Fernandez Garcia⁷, Masaki Kimura⁸, Kentaro Iwasawa⁸, John F Crary⁹, Darrell N Kotton¹⁰, Takanori Takebe¹¹, Laura M Huckins¹², Benjamin R tenOever¹³, Schahram Akbarian¹⁴, Kristen J Brennand¹⁵

Affiliations

¹ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Center for Stem Cell and Organoid Medicine (CuSTOM), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁹ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Center for Regenerative Medicine of Boston University and Boston Medical Center, Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹¹ Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Center for Stem Cell and Organoid Medicine (CuSTOM), Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
¹² Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education and Clinical Centers, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY 10468, USA.
¹³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
¹⁴ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: kristen.brennand@mssm.edu.
¹⁵ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: schahram.akbarian@mssm.edu.

Abstract

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant interindividual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly afflict healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants influence vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single-nucleotide polymorphism (rs4702), common in the population and located in the 3' UTR of the protease FURIN, influences alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can have an impact on viral infection and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs.

Keywords: FURIN rs4702; SARS-CoV-2; brain; host genetics; human induced pluripotent stem cell; neurons.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Adolescent
Adult
Animals
COVID-19 / genetics*
COVID-19 / virology
Cell Line
Chlorocebus aethiops
Clustered Regularly Interspaced Short Palindromic Repeats / genetics
Female
Furin / genetics
Genetic Predisposition to Disease / genetics*
Host-Pathogen Interactions / genetics
Humans
Induced Pluripotent Stem Cells / virology
Male
Neurons / virology
Peptide Hydrolases / genetics
Polymorphism, Single Nucleotide / genetics*
SARS-CoV-2 / pathogenicity
Vero Cells

Substances

3' Untranslated Regions
Peptide Hydrolases
Furin

Abstract

Publication types

MeSH terms

Substances

Grants and funding