Skip to main content
SpringerLink
Log in

Genome-wide epistasis study highlights genetic interactions influencing severity of COVID-19

  • COVID-19
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to life-threatening respiratory symptoms. Understanding the genetic basis of the prognosis of COVID-19 is important for risk profiling of potentially severe symptoms. Here, we conducted a genome-wide epistasis study of COVID-19 severity in 2243 patients with severe symptoms and 12,612 patients with no or mild symptoms from the UK Biobank, followed by a replication study in an independent Spanish cohort (1416 cases, 4382 controls). Our study highlighted 3 interactions with genome-wide significance in the discovery phase, nominally significant in the replication phase, and enhanced significance in the meta-analysis. For example, the lead interaction was found between rs9792388 upstream of PDGFRL and rs3025892 downstream of SNAP25, where the composite genotype of rs3025892 CT and rs9792388 CA/AA showed higher risk of severe disease than any other genotypes (P = 2.77 × 10–12, proportion of severe cases = 0.24 ~ 0.29 vs. 0.09 ~ 0.18, genotypic OR = 1.96 ~ 2.70). This interaction was replicated in the Spanish cohort (P = 0.002, proportion of severe cases = 0.30 ~ 0.36 vs. 0.14 ~ 0.25, genotypic OR = 1.45 ~ 2.37) and showed enhanced significance in the meta-analysis (P = 4.97 × 10–14). Notably, these interactions indicated a possible molecular mechanism by which SARS-CoV-2 affects the nervous system. The first exhaustive genome-wide screening for epistasis improved our understanding of genetic basis underlying the severity of COVID-19.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Data availability

Summary statistics of the GWES (41 K items P < 1 × 10–6) and GWAS (7.87 million items P < 5 × 10–8) are available from GWAS Atlas (https://ngdc.cncb.ac.cn/gwas/browse/GVP000004).

References

  1. Initiative C-HG. A first update on mapping the human genetic architecture of COVID-19. Nature. 2022;608(7921):E1-e10. https://doi.org/10.1038/s41586-022-04826-7.

    Article  CAS  Google Scholar 

  2. Karlsen TH. Understanding COVID-19 through genome-wide association studies. Nat Genet. 2022;54(4):368–9. https://doi.org/10.1038/s41588-021-00985-x.

    Article  CAS  PubMed  Google Scholar 

  3. Ellinghaus D, Degenhardt F, Bujanda L, et al. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. 2020;383(16):1522–34. https://doi.org/10.1056/NEJMoa2020283.

    Article  CAS  PubMed  Google Scholar 

  4. Nakanishi T, Pigazzini S, Degenhardt F, et al. Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality. J Clin Investig. 2021. https://doi.org/10.1172/jci152386.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bycroft C, Freeman C, Petkova D, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203–9. https://doi.org/10.1038/s41586-018-0579-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bauer W, Ulke J, Galtung N, et al. Role of cell adhesion molecules for prognosis of disease development of patients with and without COVID-19 in the emergency department. J Infect Dis. 2021;223(8):1497–9. https://doi.org/10.1093/infdis/jiab042.

    Article  CAS  PubMed  Google Scholar 

  7. Bocci M, Oudenaarden C, Sàenz-Sardà X, et al. Infection of brain pericytes underlying neuropathology of COVID-19 patients. Int J Mol Sci. 2021;22(21):11622. https://doi.org/10.3390/ijms222111622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Innocenti F, Cooper GM, Stanaway IB, et al. Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet. 2011;7(5):e1002078. https://doi.org/10.1371/journal.pgen.1002078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dobbin KK, Beer DG, Meyerson M, et al. Interlaboratory comparability study of cancer gene expression analysis using oligonucleotide microarrays. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(2 Pt 1):565–72. https://doi.org/10.1158/1078-0432.565.11.2.

    Article  CAS  Google Scholar 

  10. Lin A, Wang RT, Ahn S, Park CC, Smith DJ. A genome-wide map of human genetic interactions inferred from radiation hybrid genotypes. Genome Res. 2010;20(8):1122–32. https://doi.org/10.1101/gr.104216.109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research has been conducted using the UK Biobank Resource under Application Number 67076. The authors are grateful for the dedication, commitment and contribution of the participants, the general practitioners, pharmacists, and the staff from the UKBB. The contribution of Banca Intesa Sanpaolo is gratefully acknowledged.

Funding

This work was supported by the Strategic Priority Research Program of Chinese Academy of Sciences (XDB38010400, XDC01000000), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), National Natural Science Foundation of China (81930056), Science and Technology Service Network Initiative of Chinese Academy of Sciences (KFJ-STS-QYZD-2021–08-001, KFJ-STS-ZDTP-079). This work was also supported by Naif Arab University for Security Sciences (Grant No. PR2-10).

Author information

Author notes

  1. Shiqi Lin, Xingjian Gao and Frauke Degenhardt have contributed equally to this work.

Authors and Affiliations

  1. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China

    Shiqi Lin, Xingjian Gao, Yu Qian, Tianzi Liu & Fan Liu

  2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Shiqi Lin, Yu Qian & Fan Liu

  3. National Clinical Research Center for Kidney Diseases, Jinling Hospital, 305 East Zhongshan Road, Nanjing, China

    Xingjian Gao

  4. Institute of Clinical Molecular Biology and University Hospital of Schleswig-Holstein, Christian-Albrechts-University, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany

    Frauke Degenhardt & Andre Franke

  5. Genomes for Life-GCAT Lab., Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain

    Xavier Farre Ramon

  6. Department of Forensic Sciences, College of Criminal Justice, Naif Arab University of Security Sciences, 11452, Riyadh, Kingdom of Saudi Arabia

    Syed Sibte Hadi & Fan Liu

  7. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Manuel Romero-Gómez, Agustín Albillos, Maria Buti Ferret & Luis Bujanda

  8. Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain

    Manuel Romero-Gómez

  9. University of Sevilla, Seville, Spain

    Manuel Romero-Gómez

  10. Digestive Diseases Unit, Institute of Biomedicine of Seville, Virgen del Rocio University Hospital, University of Seville, Seville, Spain

    Manuel Romero-Gómez

  11. Hospital Clinic, University of Barcelona, and IDIBAPS, Barcelona, Spain

    Javier Fernández

  12. European Foundation for the Study of Chronic Liver Failure (EF-CLIF), Barcelona, Spain

    Javier Fernández

  13. Department of Gastroenterology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Madrid, Spain

    Agustín Albillos

  14. Liver Unit, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Maria Buti Ferret

  15. Universitat Autònoma de Barcelona, Bellatera, Spain

    Maria Buti Ferret

  16. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain

    Luis Bujanda

  17. Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Barcelona, Spain

    Antonio Julià

  18. Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy

    Rafael de Cid & Rosanna Asselta

  19. Humanitas Clinical and Research Center- IRCCS, Via Manzoni 56, 20089, Rozzano, Milan, Italy

    Rosanna Asselta

Authors
  1. Shiqi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xingjian Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frauke Degenhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tianzi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xavier Farre Ramon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Syed Sibte Hadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Romero-Gómez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Javier Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Agustín Albillos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Buti Ferret
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Luis Bujanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Antonio Julià
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rafael de Cid
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rosanna Asselta
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Andre Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Fan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: FL; Data analysis: SL, XG, FD, XFR; Data acquisition: SL, XG, FD, YQ, TL, SSH, MRG, JF, AA, MB, LB, AJ, RdC, RA, AF; Funding acquisition: FL, SH; Manuscript writing: SL, RA, FL; Supervision: FL, RA, AF; Manuscript commenting and final approval: all authors.

Corresponding authors

Correspondence to Rosanna Asselta or Fan Liu.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethics approval

Human participants: UK Biobank has approval from the North West Multi-Centre Research Ethics Committee (MREC) to obtain and disseminate data and samples from the participants (http://www.ukbiobank.ac.uk/ethics/), and these ethical regulations cover the work in this study. Written informed consent was obtained from all of the participants.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, S., Gao, X., Degenhardt, F. et al. Genome-wide epistasis study highlights genetic interactions influencing severity of COVID-19. Eur J Epidemiol 38, 883–889 (2023). https://doi.org/10.1007/s10654-023-01020-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-023-01020-5

Keywords

Search

Navigation