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

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.

FIGURE 1

Genome-wide association of COVID-19 outcomes in Serbian population: (A) severe and moderate (n = 80) versus mild (n = 48); (B) severe (n = 34) versus mild (n = 48) comparisons. Genomic coordinates of analyzed SNPs are displayed along the x-axis and the observed statistical significance of association with the disease outcome on the negative log₁₀ scale is displayed on the y-axis. SNPs with p < 0.01 are not shown on the plot. The two horizontal orange lines represent the two significance thresholds used: genome-wide significance (p < 5 × 10⁻⁸, y ≈ 7.3) and suggestive association (p < 1 × 10⁻⁵, y = 5).

FIGURE 2

LocusZoom plot showing the regional association of GWAS variant enriched loci with COVID-19 severity (severe and moderate versus mild patient group comparison). Variants in linkage disequilibrium with the lead variant are shown in color gradient indicating r² levels (hg19, 1KGP, Phase 3—November 2014, EUR): (A) 13q21.33 with rs61964606 as the lead variant; (B) 3p21.31 with rs73060324 as the lead variant; (C) 5p15.33 with rs13176661 as the lead variant; (D) 5q11.2 with rs78317595 as the lead variant; (E) 9p23 with rs1331359 as the lead variant.

FIGURE 3

LocusZoom plot showing the regional association of 3p21.31 with COVID-19 severity (severe versus mild patient group comparison), with rs35280891 as the lead variant. Variants in linkage disequilibrium with rs35280891 are shown in color gradient indicating r² levels (hg19, 1KGP, Phase 3—November 2014, EUR).