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Genetic Association Study of Mild Covid-19 Reveals Protective Variants

Written by Vered Smith, Science Writer 

A paper has been published in Nature Genetics exploring the genetic associations of mild COVID-19, using self-reported survey responses. 

The researchers surveyed patients who mostly had mild or no symptoms, and included household COVID-19 exposure as a high-risk measure. They used this to investigate susceptibility to COVID-19 infection, including comparing the genetics of exposed individuals who tested positive and exposed individuals who tested negative. The results from this study uncovered new variants that are protective against COVID-19. 

The scientists used AncestryDNA (a commercial DNA testing service) as a platform for their survey with over 50 questions asking about the participants’ COVID-19 experience. Between April and August 2020, they collected data from 736,723 participants, and investigated the genetic associations of a range of COVID-19 phenotypes. They constructed four ‘established’ phenotypes that aligned with previously studied COVID-19 phenotypes, and another four ‘expanded’ phenotypes. They then conducted a trans-ancestry GWAS meta-analysis for each of the eight phenotypes. 

Analysis of Previously Associated SNPs 

The researchers investigated the association between 12 independent SNPs identified as COVID-19 risk loci in recent COVID-19 meta-analyses, and the eight phenotypes. Eight of the 12 SNPs were replicated in at least one of the phenotypes, confirming that their phenotyping results based on self-reported studies were valid. 

Associations near ABO, the gene that determines blood type, have been observed in several COVID-19 GWASs.  In this study, the main ABO SNP (rs505922) was replicated in all four susceptibility phenotypes and one severity phenotype, verifying it as a genuine susceptibility gene.  

Additionally, three previously identified signals in the chr3p21 LZTFL1/SLC6A20 region were independently associated with a different set of phenotypes. The scientists suggested that variation in this region might affect several aspects of COVID-19 susceptibility and severity, and might represent an ‘allelic series’ between genetic variation and disease phenotype.  

Genome-wide Discovery Analysis  

In their genome-wide analysis, they found three of the ‘expanded’ phenotypes identified a larger proportion of minor alleles with protective effects, whereas the ‘established’ phenotypes identified a larger proportion of minor alleles with risk effects. This is important, as protective loss-of-function variants are good drug targets because their effects can be pharmacologically imitated.  

Future studies using mild self-reported symptoms to investigate the full profile of COVID-19 may provide insights into the mechanisms of susceptibility and severity, and enable the discovery of new therapeutic targets.

Image Credit: Canva

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