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New COVID-19 Genetic Risk Loci Discovered in Cross-Ancestry GWAS Meta-Analysis

NEW YORK – Through a large genome-wide association study meta-analysis, members of the COVID-19 Host Genetics Initiative have identified 11 previously unappreciated areas in the human genome with ties to risk of SARS-CoV-2 infection or COVID-19 disease severity.

"The biological insights gained by this expansion of the COVID-19 Host Genetic Initiative showed that increasing sample size and diversity remain a fruitful activity to better understand the human genetic architecture of COVID-19," co-senior and corresponding author Andrea Ganna, a researcher affiliated with the University of Helsinki's Institute for Molecular Medicine Finland, the Broad Institute, and Massachusetts General Hospital, and his colleagues wrote in Nature on Wednesday.

By bringing together genotyping profiles and clinical data for almost 125,600 COVID-19 cases and some 2.5 million control individuals enrolled through 60 prior studies in more than two dozen countries, the investigators flagged 23 loci with genome-wide significant ties to COVID-19 risk or severity — a set that encompassed 11 new loci.

"Expanding genomic research to include participants from around the world enabled us to test whether the effect of COVID-19-related genetic variants was markedly different across ancestry groups," the authors wrote, noting that "[g]enes at new loci, including SFTPD, MUC5B, and ACE2, reveal compelling insights regarding disease susceptibility and severity."

The different risk sites identified did not necessarily track with specific population or ancestry groups. Instead, the genetic heterogeneity seemed to stem from differences in the inclusion criteria used by different investigative groups, the team explained, noting that the majority of studies included in the GWAS meta-analysis were performed prior to widespread COVID-19 vaccine availability.

The researchers noted that their analyses were well powered to assess SARS-CoV-2 infection overall and COVID-19 hospitalization, based on data for 125,584 individuals infected with SARS-CoV-2 and almost 2.6 million controls and a subset of 25,027 individuals who were hospitalized with severe or moderate COVID-19, compared with more than 2.8 million controls.

On the other hand, they had less power to assess genetic risk for the most severe forms of COVID-19 — cases that were fatal or required respiratory support in the hospital. The latter analyses were done using data for 9,376 cases and nearly 3,200 controls.

Along with Mendelian randomization analyses of potential genetic ties to other COVID-19-related traits, the team used Bayesian modeling methods to distinguish between the 16 loci coinciding with COVID-19 disease severity and another seven loci linked to SARS-CoV-2 infection susceptibility in general.

"Although distinguishing between the two phenotypes is challenging because progression to a severe form of the disease requires susceptibility to infection in the first place, it is now evident that the genetic mechanisms involved in these two aspects of the disease can be differentiated," the authors explained.