Identification of host genetic variation predisposing to severe COVID-19 by genetics, transcriptomics and functional analyses

• Applicants: Professor Dr. Julien Gagneur; Professor Dr. Andreas Pichlmair; Professorin Dr. Eva-Christina Schulte
• Subject Area: Human Genetics ; General Genetics and Functional Genome Biology ; Virology
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466168909

• Final Report Year: 2024

Final Report Abstract

This research project aims to uncover rare genetic variants that influence the severity of COVID-19, providing insight into why people respond differently to SARS-CoV-2 infection. The goal is to identify and validate these variants to better understand the disease and guide potential treatments. Researchers have previously identified genetic variants linked to COVID-19, but data on their functional impact remains scarce. This project focuses on finding rare genetic variants with strong effects, particularly those affecting gene regulation and splicing, which are hard to predict from DNA sequences alone.First, researchers analyzed data from a hospital in Munich, Germany, involving over 200 COVID-19 patients. Previously their genome data had not reveal causal genetic factors for severe COVID-19. Here, the researchers added transcriptome data (showing which genes are active) for 148 patients to identify potential links between gene activity and disease severity. Next, the team used computational tools they had developed to detect unusual gene expression and splicing patterns in these patients. By combining rare variant data with these anomalies, they narrowed down potential genetic factors involved in severe COVID-19. A machine learning model then helped prioritize genes for further study based on their similarity to known COVID-19-related genes. 20 candidate genes were selected for functional testing in lung cells using CRISPR-Cas9 technology to see how they affected the cells' ability to fight SARS-CoV-2 infection. In doing so, genes that either increased or decreased susceptibility to the virus, which could be key to understanding why some individuals experience severe illness, were identified. Overall, the project combines genetic and transcriptomic data with computational tools and unbiased systematic functional follow-up to identify rare genetic factors influencing COVID-19 severity. This research could lead to better understanding of the disease and potentially inform new treatments or interventions for those most at risk.

Publications

• Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity. Human Genetics, 141(1), 147-173.
  Fallerini, Chiara; Picchiotti, Nicola; Baldassarri, Margherita; Zguro, Kristina; Daga, Sergio; Fava, Francesca; Benetti, Elisa; Amitrano, Sara; Bruttini, Mirella; Palmieri, Maria; Croci, Susanna; Lista, Mirjam; Beligni, Giada; Valentino, Floriana; Meloni, Ilaria; Tanfoni, Marco; Minnai, Francesca; Colombo, Francesca; Cabri, Enrico ... & Furini, Simone
  
• Interplay between the genetics of personality traits, severe psychiatric disorders and COVID-19 host genetics in the susceptibility to SARS-CoV-2 infection. BJPsych Open, 7(6).
  Heilbronner, Urs; Streit, Fabian; Vogl, Thomas; Senner, Fanny; Schaupp, Sabrina K.; Reich-Erkelenz, Daniela; Papiol, Sergi; Oraki, Kohshour Mojtaba; Klöhn-Saghatolislam, Farahnaz; Kalman, Janos L.; Heilbronner, Maria; Gade, Katrin; Comes, Ashley L.; Budde, Monika; Andlauer, Till F. M.; Anderson-Schmidt, Heike; Adorjan, Kristina; Stürmer, Til; Loerbroks, Adrian ... & Schulte, Eva C.
  
• Detailed stratified GWAS analysis for severe COVID-19 in four European populations. Human Molecular Genetics, 31(23), 3945-3966.
  Degenhardt, Frauke; Ellinghaus, David; Juzenas, Simonas; Lerga-Jaso, Jon; Wendorff, Mareike; Maya-Miles, Douglas; Uellendahl-Werth, Florian; ElAbd, Hesham; Rühlemann, Malte C.; Arora, Jatin; Özer, Onur; Lenning, Ole Bernt; Myhre, Ronny; Vadla, May Sissel; Wacker, Eike M.; Wienbrandt, Lars; Blandino, Ortiz Aaron; de Salazar, Adolfo; Garrido, Chercoles Adolfo ... & Franke, Andre
  
• Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative. PLOS Genetics, 18(11), e1010367.
  Butler-Laporte, Guillaume; Povysil, Gundula; Kosmicki, Jack A.; Cirulli, Elizabeth T.; Drivas, Theodore; Furini, Simone; Saad, Chadi; Schmidt, Axel; Olszewski, Pawel; Korotko, Urszula; Quinodoz, Mathieu; Çelik, Elifnaz; Kundu, Kousik; Walter, Klaudia; Jung, Junghyun; Stockwell, Amy D.; Sloofman, Laura G.; Jordan, Daniel M.; Thompson, Ryan C. ... & Richards, J. Brent
  
• Aberrant splicing prediction across human tissues. Nature Genetics, 55(5), 861-870.
  Wagner, Nils; Çelik, Muhammed H.; Hölzlwimmer, Florian R.; Mertes, Christian; Prokisch, Holger; Yépez, Vicente A. & Gagneur, Julien
  
• Improved detection of aberrant splicing with FRASER 2.0 and the intron Jaccard index. The American Journal of Human Genetics, 110(12), 2056-2067.
  Scheller, Ines F.; Lutz, Karoline; Mertes, Christian; Yépez, Vicente A. & Gagneur, Julien
  
• T-Cell-Dominated Immune Response Resolves Protracted SARS-CoV-2 Infection in the Absence of Neutralizing Antibodies in an Immunocompromised Individual. Microorganisms, 11(6), 1562.
  Bunse, Till; Koerber, Nina; Wintersteller, Hannah; Schneider, Jochen; Graf, Alexander; Radonic, Aleksandar; Thuermer, Andrea; von Kleist, Max; Blum, Helmut; Spinner, Christoph D.; Bauer, Tanja; Knolle, Percy A.; Protzer, Ulrike & Schulte, Eva C.
  
• Viral genome sequencing to decipher in-hospital SARS-CoV-2 transmission events. Scientific Reports, 14(1).
  Esser, Elisabeth; Schulte, Eva C.; Graf, Alexander; Karollus, Alexander; Smith, Nicholas H.; Michler, Thomas; Dvoretskii, Stefan; Angelov, Angel; Sonnabend, Michael; Peter, Silke; Engesser, Christina; Radonic, Aleksandar; Thürmer, Andrea; von Kleist, Max; Gebhardt, Friedemann; da Costa, Clarissa Prazeres; Busch, Dirk H.; Muenchhoff, Maximilian; Blum, Helmut ... & Protzer, Ulrike