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Publications

Journal Article Multicenter Study Epublish

PubMed: 40328884 DOI: 10.1038/s41598-025-00945-z

Genome-wide association study of post COVID-19 syndrome in a population-based cohort in Germany.

Sci Rep 15(1):15791

Authors: Anne-Kathrin Ruß, Stefan Schreiber, Wolfgang Lieb, J Janne Vehreschild, Peter U Heuschmann, Thomas Illig, Katharina S Appel, Maria J G T Vehreschild, Dagmar Krefting, Lennart Reinke, Alin Viebke, Susanne Poick, Stefan Störk, Jens-Peter Reese, Thomas Zoller, Lilian Krist, David Ellinghaus, Bärbel U Foesel, Christian Gieger, Bettina Lorenz-Depiereux, Martin Witzenrath, Gabriele Anton, Michael Krawczak, Jan Heyckendorf, Thomas Bahmer

Affiliations

  • Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Brunswiker Straße 10, 24113, Kiel, Germany.
  • Institute of Epidemiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
  • Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
  • Institute of Digital Medicine and Clinical Data Science, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.
  • Department I of Internal Medicine, Faculty of Medicine, University Hospital CologneUniversity of Cologne, Cologne, Germany.
  • Institute of Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.
  • Institute of Medical Data Science, University Hospital Würzburg, Würzburg, Germany.
  • Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany.
  • Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
  • Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany.
  • Medical Department 2, Center for Internal Medicine, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
  • Department of Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
  • Campus Institute Data Sciences, Göttingen, Germany.
  • Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
  • Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
  • Faculty of Health Sciences, THM University of Applied Sciences, Gießen, Germany.
  • Department of Infectious Diseases, Respiratory and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • Institute of Clinical Molecular Biology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
  • Institute of Epidemiology, Research Unit of Molecular Epidemiology, Helmholtz Munich - German Research Center for Environmental Health, Neuherberg, Germany.
  • Department of Infectious Diseases and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
  • CAPNETZ Stiftung, Hannover, Germany.
  • Medical School OWL, Bielefeld University, Bielefeld, Germany.
  • Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Brunswiker Straße 10, 24113, Kiel, Germany.
  • Airway Research Center North (ARCN), German Center for Lung Research (DZL), Großhansdorf, Germany.
  • Leibniz Lung Clinic, Kiel, Germany.

Abstract

If health impairments due to coronavirus disease 2019 (COVID-19) persist for 12 weeks or longer, patients are diagnosed with Post-COVID Syndrome (PCS), or Long-COVID. Although the COVID-19 pandemic has largely subsided in 2024, PCS is still a major health burden worldwide, and identifying potential genetic modifiers of PCS remains of great clinical and scientific interest. We therefore performed a case-control type genome-wide association study (GWAS) of three recently developed PCS (severity) scores in 2,247 participants of COVIDOM, a prospective, multi-centre, population-based cohort study of SARS-CoV-2-infected individuals in Germany. Each PCS score originally represented the weighted sum of the binary indicators of all, or a subset, of 12 PCS symptom complexes, assessed six months or later after the PCR test-confirmed SARS-CoV-2 infection of a participant. For various methodical reasons, however, the PCS scores were dichotomized along their respective median values in the present study, prior to the GWAS. Of the 6,383,167 single nucleotide polymorphisms included, various variants were found to be associated with at least one of the PCS scores, although not at the stringent genome-wide statistical significance level of 5 × 10 - 8. With p = 6.6 × 10 - 8, however, the genotype-phenotype association of SNP rs9792535 at position chr9:127,166,653 narrowly missed this threshold. The SNP is located in a region including the NEK6, PSMB7 and ADGRD2 genes which, however, does not immediately suggest an etiological connection to PCS. As regards functional plausibility, variants of a possible effect mapped to the olfactory receptor gene region (lead SNP rs10893121 at position chr11:123,854,744; p = 2.5 × 10 - 6). Impairment of smell and taste is a pathognomonic feature of both, acute COVID-19 and PCS, and our results suggest that this connection may have a genetic basis. Three other genotype-phenotype associations pointed towards a possible etiological role in PCS of cellular virus repression (CHD6 gene region), activation of macrophages (SLC7A2) and the release of virus particles from infected cells (ARHGAP44). All other gene regions highlighted by our GWAS did not relate to pathophysiological processes currently discussed for PCS. Therefore, and because the genotype-phenotype associations observed in our GWAS were generally not very strong, the complexity of the genetic background of PCS appears to be as high as that of most other multifactorial traits in humans.

MeSH

Genes, Phenotype, Multiple Chronic Conditions, Genome-Wide Association Study, Genome, Covid-19, Viruses, Genotype, Natural Science Disciplines

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