Genomics analysis on why Covid-19 affects people so differently

Last year scientists from around the world undertook genetic analysis to uncover the genetic factors influencing why some Covid-19 patients develop severe, life-threatening disease requiring hospitalisation, while others escape with mild symptoms or none at all. A comprehensive summary of their findings to date, published in Nature, reveals 13 loci, or locations in the human genome, that are strongly associated with infection or severe Covid-19.

These results come from one of the largest genome-wide association studies ever performed, which includes nearly 50,000 Covid-19 patients and two million uninfected controls. The findings could help provide targets for future therapies and illustrate the power of genetic studies in learning more about infectious disease.

This global effort, called the Covid-19 Host Genomics Initiative, was founded in March 2020 by Andrea Ganna, Group Leader at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki and Mark Daly, Director of FIMM and institute member at the Broad Institute of MIT and Harvard. The initiative has grown and is said to be one of the most extensive collaborations in human genetics and currently includes more than 3,300 authors and 61 studies from 25 countries.

For the analysis, the consortium pooled clinical and genetic data from the nearly 50,000 patients in their study who tested positive for the virus, and two million controls across numerous biobanks, clinical studies and direct-to-consumer genetic companies, such as 23andMe.

The biobank housed in the Colorado Center for Personalised Medicine (CCPM), a partnership between non-profit health system UCHealth and the University of Colorado Anschutz Medical Campus, was one of four biobanks in the United States that contributed to these studies. The CCPM biobank is actively generating genomic data and combining insights with the electronic health record, comprising one of the largest institutional biobanks in the United States. Currently, CCPM has more than 180,000 research participants consented with active recruitment to develop a comprehensive clinical and research resource for hundreds of thousands of UCHealth patients.

“We were honoured to take part in a study allowing us to understand genetic processes relevant to the Covid-19 pandemic, and to leverage the great resource that is the CCPM in such a collaborative endeavour,” said Chris Gignoux, Director of Research at CCPM and associate professor in the division of Biomedical Informatics and Personalised Medicine at the University of Colorado School of Medicine.

Of the 13 loci identified so far by the team, two had higher frequencies among patients of East Asian or South Asian ancestry than in those of European ancestry, underscoring the importance of diversity in genetic datasets. “We’ve been much more successful than past efforts in sampling genetic diversity because we’ve made a concerted effort to reach out to populations around the world,” said Daly, Director of FIMM and institute member at the Broad Institute of MIT and Harvard.

The team highlighted one of these two loci in particular, near the FOXP4 gene, which is linked to lung cancer. The FOXP4 variant associated with severe Covid-19 increases the gene’s expression, suggesting that inhibiting the gene could be a potential therapeutic strategy. Other loci associated with severe Covid-19 included DPP9, a gene also involved in lung cancer and pulmonary fibrosis, and TYK2, which is implicated in some autoimmune diseases.

“We’d like to aim to get a good handful of very concrete therapeutic hypotheses in the next year,” Daly said. “Realistically, we will most likely be addressing Covid-19 as a serious health concern for a long time. Any therapeutic that emerges this year, for example from repurposing an existing drug based on clear genetic insights, would have a great impact.”

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