Unraveling the protective genetic architecture of COVID-19 in the Brazilian Amazon

Abstract

Despite all the efforts acquired in four years of the COVID-19 pandemic, the path to a full understanding of the biological mechanisms involved in this disease remains complex. This is partly due to a combination of factors, including the inherent characteristics of the infection, socio-environmental elements, and the variations observed within both the viral and the human genomes. Thus, this study aimed to investigate the correlation between genetic host factors and the severity of COVID-19. We conducted whole exome sequencing (WES) of 124 patients, categorized into severe and non-severe groups. From the whole exome sequencing (WES) association analysis, four variants (rs1770731 in CRYBG1, rs7221209 in DNAH17, rs3826295 in DGKE, and rs7913626 in CFAP46) were identified as potentially linked to a protective effect against the clinical severity of COVID-19, which may explain the less severe impact of COVID-19 on the Northern Region. Our findings underscore the importance of carrying out more genomic studies in populations living in the Amazon, one of the most diverse from the point of view of the presence of rare and specific alleles. To our knowledge, this is the first WES study of admixed individuals from the Brazilian Amazon to investigate genomic variants associated with the clinical severity of COVID-19.

Keywords: SARS-CoV-2; Amazon; COVID-19; Clinical severity; WES.

Fig. 1

Supervised analysis of the population structuring patterns present in the study sample. WAFR - West Africa (YRI), EUR - Europe (IBS), AMI - Indigenous of America and COV - COVID-19 affected patients.

Fig. 2

PCA analysis of genomic ancestry based on allele frequency present in the study subjects and in the following subjects: CAS - Central Asia, EAFR - East Africa, OCE - Oceania, EUR - Europe, MDL - Middle East, ADMX - Mixed Populations of the Americas, EAS - East Asia, AMR - Amerindians, WAFR - West Africa, SAS - South/Southeast Asia, COV - COVID-19 patients.

Fig. 3

Manhattan plot of the WES of 130 participants (non-severe (n = 56) vs. severe (n = 68)), highlighting four peaks with possibly association signals for severe cases of COVID-19. The WES 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 < 5 × 10-4).

Fig. 4

The PRS distribution of the associated variants among the study populations (sCOV, nsCOV and AMI) and continental populations (AFR, AMR, EUR, EAS, and SAS).

Fig. 5

Flowchart of the study methodology. DNA extraction and Whole Exome Sequencing (WES) were performed in 124 samples, divided in two groups: 68 patients with severe COVID-19 (sCOV) and 56 patients with non-severe COVID-19 (nsCOV). The figure also shows the main steps used in the exome’s pipeline. In dark blue, reads’s quality treatment by trimming and filtering. In lilac, mapping reads using a reference genome. In red, variant calling by DeepVariant pipeline. In orange, samples’ quality treatment. In gray, population structure analysis. And in light blue, association tests analysis in R software.

Fig. 6

Formula used to calculate the population polygenic risk score. PRS: Polygenic Risk Score; p: population; e: effect allele; OR: OddsRatio; i: individual.