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GEN-COVID study uses whole-exome sequencing to unravel COVID-19 susceptibility

A team of researchers from Italy have identified multiple genetic variants that could play a role in determining the severity of symptoms associated with COVID-19.

The results are the outcome of an ongoing study called GEN-COVID, which involves 35 hospitals across Italy. The team presented their findings during the European Society of Human Genetics virtual conference last week.

The project is being led by Alessandra Renieri, the director of the medical genetics unit at the University Hospital of Siena, where she provided an overview of the study. According to Renieri, the GEN-COVID project aims to develop a patient registry and biobank for studying COVID-19 and will focus on understanding the genetic and molecular basis of susceptibility and help further understand the genetic profiles of patients to help guide future therapy decisions.

The project began by collecting samples from around Italy on March 16th. The researchers also collected phenotypic information about the patients using questionnaires with 160 clinical questions and combined this with whole-exome sequencing data. Reneiri says that in that way, they were able to not only able to capture “heterozygous and homozygous germline mutations, but also somatic variants and multicopy genes”.

The pilot phase of the study involved 35 cases and 150 controls from hospitals in Tuscany to test the hypothesis that susceptibility was due to common factors, but this failed to show significant results for common genes, except for the OR4C5 and ZNF717 genes.

This was an unexpected result and so they used autism spectrum disorder research as an example, reanalysed the cohort to look for rarer mutations that may be impacting clinical outcome. They used this approach to identify for each patient about three pathogenic mutations involved in virus infection susceptibility. Renieri said that whole-exome sequencing showed that a combination of common and rare, or even private variants, is responsible for COVID-19 susceptibility and severity.

The team then conducted the first validation phase, which had 131 cases and 250 controls from a network of 35 hospitals and clinics. They then used a variety of machine learning tools which generated a larger cache of genes of interest but the researchers felt that different variations were more likely to underpin disease susceptibility in different individuals, and using other machine learning tools they were able to identify rare variants in genes such as JAK2 and CCDC114 in some cases.

A second validation phase of the study is now underway which will involve 2000 cases and 3000 controls. Renieri said that about 500 cases of the second validation phase have already been run and that by August they expect to have collected the remaining samples for the study.

As well as looking at the common and rare variants that may impact disease susceptibility, the researchers will also look at gender as men have been having more severe reactions to the virus.

The outcome of GEN-COVID could have implications for healthcare, the repurposing of medicines for treatment and drug development efforts and the biobank that is developed by the project will be made accessible to academic and industry partners.