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Genetics & COVID-19 Pandemic Are Focus of Special Session at ASHG 2020 Virtual Annual Meeting (October 27-30); On Wednesday, Six Researchers Reported Recent Data on Susceptibility and Severity in “Late-Breaking COVID-19 Research Update” Session

With the COVID-19 pandemic still raging worldwide, members of the American Society of Human Genetics (ASHG) are working to understand how the virus spreads and infects people, why there is so much variability in susceptibility and severity, and where to look for potential therapeutics. On Wednesday, October 28, six researchers presented recent results of several studies relevant to the current pandemic at the ASHG 2020 Virtual Annual Meeting (October 27-30). So far, this meeting has attracted over 6,000 registrants from more than 80 countries around the world. Approximately 1,000 of these registrants tuned in for this special timely session titled “Late-Breaking COVID-19 Research Update.” COVID-19 symptoms vary widely, ranging from asymptomatic in some patients to fatal in others. Elucidating the role of human genetic variation could result in a better understanding of susceptibility to infection, as well as of differences in patient presentation and outcomes. Three studies addressed human genetics and COVID-19 susceptibility and severity. In the first, Jack Kosmicki, Regeneron Genetics Center, and colleagues presented the results of the largest trans-ancestry exome sequencing study of COVID-19 to date. In a replication of previous findings, the researchers identified the 3p21.31 locus and suggested it contributes to variability in severity. The group failed to replicate an association between COVID-19 and the ABO locus, suggesting that the previous finding may have been a false positive. Beyond previously reported associations, Kosmicki and colleagues also identified three novel loci and three genes associated with COVID-19. In the second report, Andrea Ganna, Institute for Molecular Medicine Finland, and colleagues, reported a meta-analysis from the COVID-19 Host Genetics Initiative, a collaborative, international effort to bring together the human genetics community to generate, share, and analyze data related to COVID-19. The research team identified a genetic variant on chromosome 3 that was strongly associated with disease severity, but not susceptibility. Like all of the Initiative’s results, these are immediately available on its website (https://www.covid19hg.org/) without any restriction of use. The third study, presented by Gita Pathak, Yale University, suggests the involvement of several biological mechanisms in COVID-19 induced hospitalization. In addition to identifying six COVID-19-associated genes in two chromosomic regions, the researchers uncovered associations with laboratory readings--such as LDL cholesterol, cortisol levels, and monocyte count--that are consistent with markers of inflammation.

Together, these three studies point to exciting areas for future research. For instance, all three groups identified chromosome 3 as a susceptibility locus, but further work is needed to work out the mechanism and details.

In another COVID-19 related study, A. Rouf Banday, National Cancer Institute, National Institutes of Health, reported the discovery of a novel variant of the cell-surface enzyme ACE2, which the virus SARS-CoV-2 uses to enter target cells. The researchers showed that this variant called dACE2, but not ACE2, is induced by interferons and viral infections, including SARS-CoV-2. The findings are important to consider for future therapeutic strategies and understanding susceptibility and outcomes of COVID-19.

Brendan O’Connell, Oregon Health & Science University, and colleagues, demonstrated that rapid sequencing of viral genomes can enable the identification of specific transmission chains within a community by tracing mutations that arise over time. The researchers determined the number of introductions and spread of COVID-19 in Oregon during the first six months of the outbreak. Overall, the data strongly support the conclusion that the major source of new viral introductions in Oregon are from domestic travel.

Finally, Tomiko Oskotsky, University of California San Francisco, discussed the application of a computational drug repositioning pipeline to identify existing drugs that may have novel therapeutic uses in COVID-19. The results thus far are encouraging, with validation experiments showing that 9 of the 12 hits tested to date have measurable antiviral activity against SARS-CoV-2.

REFERENCES

Banday, A.R., et al. (Date). Abstract: The discovery of a novel primate-specific and inducible truncated isoform of ACE2 and its implications for SARS-CoV-2 infection. Presented at the American Society of Human Genetics 2020 Virtual Meeting.
Ganna, A., et al. (Date). Abstract: The COVID-19 host genetics initiative identifies genetic factors associated with COVID-19 susceptibility, severity, and outcomes. Presented at the American Society of Human Genetics 2020 Virtual Meeting.

Kosmicki, J., et al. (Date). Abstract: Trans-ancestry imputation and exome sequencing of 868,021 individuals identifies 4 loci and 3 genes associated with Covid-19 susceptibility and hospitalization. Presented at the American Society of Human Genetics 2020 Virtual Meeting.

O’Connell, B., et al. (Date). Abstract: Genomic surveillance of SARS-CoV-2 in Oregon from February-July 2020 identifies at least 25 independent introductions, transmission dynamics of a healthcare workplace superspreading event, and recurrent deletions removing ORF7a from the viral genome. Presented at the American Society of Human Genetics 2020 Virtual Meeting.

Ostotsky, T., et al. (Date). Abstract: Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19. Presented at the American Society of Human Genetics 2020 Virtual Meeting.

Pathak, G., et al. (Date). Abstract: Integrative analyses with large-scale COVID-19 GWAS identifies susceptibility genes underlying hospitalized outcomes. Presented at the American Society of Human Genetics 2020 Virtual Meeting.

AMERICAN SOCIETY OF HUMAN GENETICS (ASHG)

Founded in 1948, the American Society of Human Genetics is the primary professional membership organization for human genetics specialists worldwide. Its nearly 8,000 members include researchers, academicians, clinicians, laboratory practice professionals, genetic counselors, nurses, and others with an interest in human genetics. The Society serves scientists, health professionals, and the public by providing forums to: (1) share research results through the ASHG Annual Meeting and in The American Journal of Human Genetics; (2) advance genetic research by advocating for research support; (3) educate current and future genetics professionals, health care providers, advocates, policymakers, educators, students, and the public about all aspects of human genetics; and (4) promote genetic services and support responsible social and scientific policies. For more information, visit: http://www.ashg.org.

[ASHG press release] [ASHG 2020 Virtual Annual Meeting]