Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population

Marko Zecevic; Nikola Kotur; Bojan Ristivojevic; Vladimir Gasic; Vesna Skodric-Trifunovic; Mihailo Stjepanovic; Goran Stevanovic; Lidija Lavadinovic; Branka Zukic; Sonja Pavlovic; Biljana Stankovic

doi:10.3389/fgene.2022.911010

Genome-Wide Association Study of COVID-19 Outcomes Reveals Novel Host Genetic Risk Loci in the Serbian Population

Front Genet. 2022 Jul 14:13:911010. doi: 10.3389/fgene.2022.911010. eCollection 2022.

Authors

Marko Zecevic^{1

2}, Nikola Kotur¹, Bojan Ristivojevic¹, Vladimir Gasic¹, Vesna Skodric-Trifunovic^{3

4}, Mihailo Stjepanovic^{3

4}, Goran Stevanovic^{4

5}, Lidija Lavadinovic⁵, Branka Zukic¹, Sonja Pavlovic¹, Biljana Stankovic¹

Affiliations

¹ Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
² Seven Bridges, Boston, MA, United States.
³ Clinic of Pulmonology, Clinical Centre of Serbia, Belgrade, Serbia.
⁴ Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
⁵ Clinic for Infectious and Tropical Diseases, Clinical Centre of Serbia, Belgrade, Serbia.

Abstract

Host genetics, an important contributor to the COVID-19 clinical susceptibility and severity, currently is the focus of multiple genome-wide association studies (GWAS) in populations affected by the pandemic. This is the first study from Serbia that performed a GWAS of COVID-19 outcomes to identify genetic risk markers of disease severity. A group of 128 hospitalized COVID-19 patients from the Serbian population was enrolled in the study. We conducted a GWAS comparing (1) patients with pneumonia (n = 80) against patients without pneumonia (n = 48), and (2) severe (n = 34) against mild disease (n = 48) patients, using a genotyping array followed by imputation of missing genotypes. We have detected a significant signal associated with COVID-19 related pneumonia at locus 13q21.33, with a peak residing upstream of the gene KLHL1 (p = 1.91 × 10^-8). Our study also replicated a previously reported COVID-19 risk locus at 3p21.31, identifying lead variants in SACM1L and LZTFL1 genes suggestively associated with pneumonia (p = 7.54 × 10^-6) and severe COVID-19 (p = 6.88 × 10^-7), respectively. Suggestive association with COVID-19 pneumonia has also been observed at chromosomes 5p15.33 (IRX, NDUFS6, MRPL36, p = 2.81 × 10^-6), 5q11.2 (ESM1, p = 6.59 × 10^-6), and 9p23 (TYRP1, LURAP1L, p = 8.69 × 10^-6). The genes located in or near the risk loci are expressed in neural or lung tissues, and have been previously associated with respiratory diseases such as asthma and COVID-19 or reported as differentially expressed in COVID-19 gene expression profiling studies. Our results revealed novel risk loci for pneumonia and severe COVID-19 disease which could contribute to a better understanding of the COVID-19 host genetics in different populations.

Keywords: GWAS; SARS-CoV-2; genetic markers; pneumonia; severe disease.