Genome-wide association study of hospitalized COVID-19 patients in the United Arab Emirates

Abstract

Background: The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. The objective of this manuscript is to conduct a trans-ancestry genome wide association study (GWAS) meta-analysis of COVID-19 severity to improve the understanding of potentially causal targets for SARS-CoV-2.

Methods: This cross-sectional study recruited 646 participants in the UAE that were divided into two phenotypic groups based on the severity of COVID-19 phenotypes, hospitalized (n=482) and non-hospitalized (n=164) participants. Hospitalized participants were COVID-19 patients that developed acute respiratory distress syndrome (ARDS), pneumonia or progression to respiratory failure that required supplemental oxygen therapy or mechanical ventilation support or had severe complications such as septic shock or multi-organ failure. We conducted a trans-ancestry meta-analysis GWAS of European (n=302), American (n=102), South Asian (n=99), and East Asian (n=107) ancestry populations. We also carried out comprehensive post-GWAS analysis, including enrichment of SNP associations in tissues and cell-types, expression quantitative trait loci and differential expression analysis.

Findings: Eight genes demonstrated a strong association signal: VWA8 gene in locus 13p14·11 (SNP rs10507497; p=9·54 x10^-7), PDE8B gene in locus 5q13·3 (SNP rs7715119; p=2·19 x10^-6), CTSC gene in locus 11q14·2 (rs72953026; p=2·38 x10^-6), THSD7B gene in locus 2q22·1 (rs7605851; p=3·07x10^-6), STK39 gene in locus 2q24·3 (rs7595310; p=4·55 x10^-6), FBXO34 gene in locus 14q22·3 (rs10140801; p=8·26 x10^-6), RPL6P27 gene in locus 18p11·31 (rs11659676; p=8·88 x10^-6), and METTL21C gene in locus 13q33·1 (rs599976; p=8·95 x10^-6). The genes are expressed in the lung, associated to tumour progression, emphysema, airway obstruction, and surface tension within the lung, as well as an association to T-cell-mediated inflammation and the production of inflammatory cytokines.

Interpretation: We have discovered eight highly plausible genetic association with hospitalized cases in COVID-19. Further studies must be conducted on worldwide population genetics to facilitate the development of population specific therapeutics to mitigate this worldwide challenge.

Funding: This review was commissioned as part of a project to study the host cell receptors of coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).

Keywords: COVID-19; GWAS; Genetics; SARS-CoV-2.

Fig. 1

Manhattan plot of the trans-ancestry GWAS meta-analysis of 610 participants (non-hospitalized (n=157) vs. hospitalized (n=453)), highlighting eight peaks with moderate association signal for hospitalized cases of COVID-19. The GWAS analysis results are shown on the y-axis as -log10 (p-value) and on the x-axis is the chromosomal location. The red horizontal line illustrated the suggestive genome-wide association threshold (p<5x10^-5).

Fig. 2

Regional plots for association of genotyped and imputed SNPs in the trans-ancestry GWAS meta-analysis in association to hospitalized COVID-19. SNPs are plotted according to their chromosomal position (NCBI Build 37) with -log10 p-values on the y-axis, and the relative location of the annotated genes and the direction of transcription are shown in the lower portion of the Fig. The most strongly associated SNP is shown as a small purple circle. Linkage disequilibrium (LD; R² values) between the lead SNP and the other SNPs is indicated using red colours. The colour scheme indicated the LD displayed as r² values between all SNPs and the top-ranked SNP in each plot. Top-ranked SNPs are shown as purple diamonds in the top of each chromosomal locus: (a) 13q14·11, (b) 5q13·3, (c)11q14·2, (d) 2q22·1, (e) 2q24·3, (f) 14q22·3, (g) 18p11·31, and (h) 13q33·1. The blue lines represent the estimated recombination rates. Plots are generated using LDlink.

Fig. 3

Functional annotation and eQTL expression in the Lung tissue obtained from Human Protein Atlas database: (a) immunologic signature of the proportion of overlapping genes (FBXO34, STK39, PDE8B); b) heatmap of GTEx v8 30 general tissue types and the average expression per label (log2 transformed); c) VWA8 gene in locus 13p14·11, (d) PDE8B gene in locus 5q13·3, (e) CTSC gene in locus 11q14·2, (f) STK39 gene in locus 2q24·3; (g) FBXO34 gene in locus 14q22·3.