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

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 9 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 inter-individual variability in COVID-19 phenotypes.

DOI: 10.1016/j.isci.2022.103760


Other Contributors

Nikhil Shri Sahajpal 1, Chi-Yu Jill Lai 2, Alex Hastie 2, Ashis K Mondal 1, Siavash Raeisi Dehkordi 3, Caspar I van der Made 4, Olivier Fedrigo 5, Farooq Al-Ajli 5, Sawan Jalnapurkar 6, Marta Byrska-Bishop 7, Rashmi Kanagal-Shamanna 8, Brynn Levy 9, Maximilian Schieck 10, Thomas Illig 10 11, Silviu-Alin Bacanu 12, Janet S Chou 13, Adrienne G Randolph 14 15, Amyn M Rojiani 1, Michael C Zody 7, Catherine A Brownstein 16, Alan H Beggs 16, Vineet Bafna 3, Erich D Jarvis 5 17 18, Alexander Hoischen 4, Alka Chaubey 1 2, Ravindra Kolhe 1, COVID19hostgenomesv consortium

1 Department of Pathology, Medical College of Georgia, Augusta University, GA, 30912, U.S.A.
2 Bionano Genomics, Inc., San Diego, CA, 92121, U.S.A.
3 Department of Computer Science and Engineering, University of California at San Diego, CA, 92093, U.S.A.
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, Nijmegen, 6525GA, 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, U.S.A.
7 New York Genome Center, New York, NY, 10013, U.S.A.
8 Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, U.S.A.
9 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, 10032, U.S.A.
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, VA, 23284, U.S.A.
13 Division of Immunology, Boston Children’s Hospital, Boston, MA, 02115, U.S.A.
14 Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Boston, MA, 02115, U.S.A.
15 Departments of Anesthesia and Pediatrics, Harvard Medical School, Boston, MA, 02115, U.S.A.
16 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, U.S.A.
17 Laboratory of Neurogenetics of Language, The Rockefeller University, New York, NY, 10065, USA.
18 Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.