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AncestryDNA Study Defines Expanded COVID-19 Phenotypes, Explores Ties With Genetic Loci

NEW YORK – A team led by investigators at AncestryDNA has described eight distinct COVID-19 outcome phenotypes and explored their genetic contributors, based on a large genome-wide association study of almost 740,000 individuals.

"[T]he AncestryDNA self-reported dataset allowed a complementary analysis of more granular phenotypes in a population enriched for mild outcomes compared to clinically ascertained studies enriched for severe outcomes," senior and corresponding author Kristin Rand, a researcher with AncestryDNA in San Francisco, and her colleagues wrote. "We found promising evidence that exploring new phenotypes in such populations will yield new genetic associations, particularly those that confer protection against the novel coronavirus SARS-CoV-2."

As they reported in Nature Genetics on Monday, the researchers used survey data for more than 736,700 research-consented AncestryDNA customers to come up with the more refined COVID-19 phenotypes, creating phenotype clusters that encompassed self-reported experiences and outcomes in individuals infected with or exposed to SARS-CoV-2.

"In this work, we used the self-reported survey responses to construct four phenotypes that align with previously studied COVID-19 phenotypes plus four additional, 'expanded' phenotypes that would be challenging to collect at large scale using typical hospital/clinical case ascertainment," the authors explained.

From there, the team brought in array-based genotyping profiles for the survey participants for genome-wide association study meta-analyses within and across individuals' ancestry groups, along with replication analyses centered on 12 COVID-19-related loci reported in past studies.

Three phenotype clusters related to hospitalization and disease severity showed comparable associations to previously reported risk loci, while three clusters related to COVID-19 susceptibility after exposure showed relationships to distinct subsets of the risk loci. Two more phenotype clusters had more tenuous ties to the previously reported loci, the researchers noted, perhaps owing to additional genetic associations that have not yet been uncovered.

Although the new GWAS analyses did not lead to new loci with genome-wide significant ties to the phenotypes considered, the team said additional studies digging into at least three of the new "expanded" COVID-19 phenotypes may yield new variants that protect against COVID-19 infections or severe disease.

"The results of this multi-phenotype analysis reproduce the majority of associations identified by previous COVID-19 GWASs, shed light on whether previously identified loci associate with COVID-19 susceptibility or severity, and suggest that certain 'expanded' phenotype definitions may yield new loci of therapeutic relevance," the authors reported.

More broadly, they noted that "[f]urther studies that leverage mild and subclinical self-reported symptoms to probe the full symptom profile of disease may yield new insights into this disease and other diseases with complex symptom profiles, ultimately helping uncover disease mechanisms and providing potential therapeutic targets."