Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

Nikhil Shri Sahajpal; Chi-Yu Jill Lai; Alex Hastie; Ashis K Mondal; Siavash Raeisi Dehkordi; Caspar I van der Made; Olivier Fedrigo; Farooq Al-Ajli; Sawan Jalnapurkar; Marta Byrska-Bishop; Rashmi Kanagal-Shamanna; Brynn Levy; Maximilian Schieck; Thomas Illig; Silviu-Alin Bacanu; Janet S Chou; Adrienne G Randolph; Amyn M Rojiani; Michael C Zody; Catherine A Brownstein; Alan H Beggs; Vineet Bafna; Erich D Jarvis; Alexander Hoischen; Alka Chaubey; Ravindra Kolhe; COVID19hostgenomesv Consortium

doi:10.1016/j.isci.2022.103760

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19

iScience. 2022 Feb 18;25(2):103760. doi: 10.1016/j.isci.2022.103760. Epub 2022 Jan 10.

Authors

Nikhil Shri Sahajpal¹, Chi-Yu Jill Lai², Alex Hastie², Ashis K Mondal¹, Siavash Raeisi Dehkordi³, Caspar I van der Made⁴, Olivier Fedrigo⁵, Farooq Al-Ajli⁵, Sawan Jalnapurkar⁶, Marta Byrska-Bishop⁷, Rashmi Kanagal-Shamanna⁸, Brynn Levy⁹, Maximilian Schieck¹⁰, Thomas Illig^{10

11}, Silviu-Alin Bacanu¹², Janet S Chou¹³, Adrienne G Randolph^{14

15}, Amyn M Rojiani¹, Michael C Zody⁷, Catherine A Brownstein¹⁶, Alan H Beggs¹⁶, Vineet Bafna³, Erich D Jarvis^{5

17

18}, Alexander Hoischen⁴, Alka Chaubey^{1

2}, Ravindra Kolhe¹; COVID19hostgenomesv Consortium

Affiliations

¹ Department of Pathology, Medical College of Georgia, Augusta University, 1120 15th Street, BF-207, Augusta, GA 30912, USA.
² Bionano Genomics, Inc., San Diego, CA 92121, USA.
³ Department of Computer Science and Engineering, University of California at San Diego, San Diego, CA 92093, USA.
⁴ Department of Human Genetics, Radboud University Medical Center for Infectious Diseases (RCI), Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, and Radboud Expertise Center for Immunodeficiency and Autoinflammation, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
⁵ Vertebrate Genome Lab, The Rockefeller University, New York, NY 10065, USA.
⁶ Department of Medicine, Medical College of Georgia, Augusta University, GA 30912, USA.
⁷ New York Genome Center, New York, NY 10013, USA.
⁸ Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
⁹ Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA.
¹⁰ Department of Human Genetics, Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover 30625, Germany.
¹¹ Hannover Unified Biobank (HUB), Hannover 30625, Germany.
¹² Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23284, USA.
¹³ Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁴ Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁵ Departments of Anesthesia and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁷ Laboratory of Neurogenetics of Language, The Rockefeller University, New York, NY 10065, USA.
¹⁸ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Abstract

Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in nine patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with interindividual variability in COVID-19 phenotypes.

Keywords: Genetic sample; Genomics; Virology.

Grants and funding

R01 GM114362/GM/NIGMS NIH HHS/United States