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Genetic Factors Increase Risk for Severe COVID-19 Illness: Study

Nancy Cox, PhD

A massive worldwide collaboration including researchers from Vanderbilt University Medical Center (VUMC) has identified several genetic factors associated with SARS-CoV-2 infection and severe COVID-19 illness.

The findings from nearly 50,000 COVID-19 patients and 2 million uninfected controls, published July 8 in the journal Nature, could lead to new treatments and demonstrates the power of genetic studies to respond to the worldwide pandemic.

More than 3,500 scientists from 25 countries are participating in the effort, called the COVID-19 Host Genetics Initiative (HGI), which was founded in March 2020 by Andrea Ganna, PhD, and Mark Daly, PhD, of the Institute for Molecular Medicine Finland at the University of Helsinki and the Broad Institute of MIT and Harvard.

Genome-wide association studies (GWAS) can help identify genetic factors in patients that may have increased their risk for becoming infected by and severely ill from SARS-CoV-2, the virus that causes COVID-19.

GWAS results from genetic samples stored VUMC's biobank, BioVU, were provided to the HGI by analysis team leaders Nancy Cox, PhD, the Mary Phillips Edmonds Gray Professor of Genetics and director of the Vanderbilt Genetics Institute, and associate professors of Medicine Jennifer "Piper" Below, PhD, and Lea Davis, PhD.

The HGI study identified 13 loci, or locations on the human genome, that are strongly associated with SARS-CoV-2 infection or severe illness. Two loci were found more frequently among patients of East Asian or South Asian ancestry than among those of European ancestry.

One of the two loci is near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe COVID-19 increases the expression of the gene, suggesting that inhibiting it could be a potential therapeutic strategy.

Other loci associated with severe COVID-19 included DPP9, a gene also linked to lung cancer and pulmonary fibrosis, and TYK2, implicated in some autoimmune diseases. Smoking and high body mass index also were identified as causal risk factors for severe COVID-19 illness.

"Realistically, we will most likely be addressing COVID-19 as a serious health concern for a long time," Daly said in a news release. "Any therapeutic that emerges this year, for example from repurposing an existing drug based on clear genetic insights, would have a great impact."

"The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks," the researchers concluded. "This working model of international collaboration provides a blueprint for future genetic discoveries in the event of pandemics or for any complex human disease."

VUMC is a leader in the development of biobanks and electronic health records. BioVU is one of the largest such biobanks in the world at a single center.

"Our ability at Vanderbilt to develop algorithms on the fly and to create and share protocols can be very helpful in times like these," Cox said last year, when VUMC joined the initiative.

Below, co-principal investigator of the Cameron County Hispanic Cohort, provided GWAS results from the cohort study to the HGI. Cameron County, Texas, which is on the Texas-Mexico border, had one of the nation's highest rates of COVID-19 last year.

Davis serves on the HGI Phenotype Steering Group and ran the BioVU COVID-19 GWAS with Annika B. Faucon, a VUMC graduate student in Human Genetics, and Megan Shuey, PhD, a postdoctoral research fellow in the Division of Genetic Medicine, which Cox directs.

Other Vanderbilt faculty members who have participated in the COVID-19 HGI include:

  • Elizabeth Phillips, MD, the John A. Oates Chair in Clinical Research, professor of Medicine and an internationally known expert in drug hypersensitivity;
  • Simon Mallal, MBBS, the Major E.B. Stahlman Chair in Infectious Diseases and Inflammation, professor of Medicine, and scientific director of the Vanderbilt Technologies for Advanced Genomics (VANTAGE)core; and
  • Lisa Bastarache, MS, research assistant professor of Biomedical Informatics who with Biomedical Informatics Professor Josh Peterson, MD, MPH, is developing an electronic health record-based COVID research registry.


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