COVID-19, caused by the new pandemic coronavirus, is strangely—and tragically—selective. Only some infected people get sick, and although most of the critically ill are elderly or have complicating problems such as heart disease, some killed by the disease are previously healthy and even relatively young. Researchers are now gearing up to scour the patients' genomes for DNA variations that explain this mystery. The findings could be used to identify those most at risk of serious illness and those who might be protected, and they might also guide the search for new treatments.
The projects range from ongoing studies with DNA for many thousands of participants, some now getting infected with the coronavirus, to new efforts that are collecting DNA from COVID-19 patients in hard-hit places such as Italy. The goal is to compare the DNA of people who have serious cases of COVID-19 (which stands for coronavirus disease 2019)—but no underlying disease like diabetes, heart or lung disease—with those with mild or no disease. "We see huge differences in clinical outcomes and across countries. How much of that is explained by genetic susceptibility is a very open question," says geneticist Andrea Ganna of the University of Helsinki's Institute for Molecular Medicine Finland (FIMM).
It's hard to predict what will pop out from these gene hunts, some researchers say. But there are obvious suspects, such as the gene coding for the cell surface protein angiotensin-converting enzyme 2 (ACE2), which the coronavirus uses to enter airway cells. Variations in the ACE2 gene that alter the receptor could make it easier or harder for the virus to get into cells, says immunologist Philip Murphy of the National Institute of Allergy and Infectious Diseases, whose lab identified a relatively common mutation in another human cell surface protein, CCR5, that makes some people highly resistant to HIV.
Ganna heads up a major effort to pool COVID-19 patients' genetic data from around the world. The idea "came quite spontaneously" about 2 weeks ago when "everyone was sitting at their computers watching this crisis," says Ganna, who is also affiliated with the Broad Institute, a U.S. genomic powerhouse.
He and FIMM Director Mark Daly quickly created a website for their project, the COVID-19 Host Genetics Initiative, and reached out to colleagues who run large biobank studies that follow thousands of volunteers for years to look for links between their DNA and health. At least a dozen biobanks, mostly in Europe and the United States, have expressed interest in contributing COVID-19 data from participants who agreed to this. Among them are FinnGen, which has DNA samples and health data for 5% of the 5 million–person Finnish population, and the 50,000-participant biobank at the Icahn School of Medicine at Mount Sinai.
The UK Biobank, one of world's largest with DNA data for 500,000 participants, also plans to add COVID-19 health data from participants to its data set, the project tweeted this month. And the Icelandic company deCODE Genetics, which is helping test much of the nation's population to see who is infected with the new coronavirus, has received government permission to add these data and any subsequent COVID-19 symptoms to its database, which contains genome and health data on half of Iceland's 364,000 inhabitants, says its CEO Kári Stefánsson. "We will do our best to contribute to figuring this out," Stefánsson says.
Another effort to identify protective or susceptibility DNA variants is the Personal Genome Project led by Harvard University's George Church, which recruits people willing to share their full genome, tissue samples, and health data for research. Earlier this month, it sent questionnaires to its thousands of participants, asking about their COVID-19 status. More than 600 in the United States responded within 48 hours. "It seems that most people want to do their part," says Church, whose group isn't yet part of Ganna's collaboration.
Other researchers working with Ganna's initiative are recruiting COVID-19 patients directly within hospitals for such genomics studies. Italian geneticist Alessandra Renieri of the University of Siena expects at least 11 hospitals in the nation to give ethics approval for her team to collect DNA samples from willing patients. "It is my opinion that [host] genetic differences are a key factor … for susceptibility to severe acute pneumonia," Renieri says.
Pediatrics researcher Jean-Laurent Casanova at the Rockefeller University, who specializes in identifying rare genes that can make healthy young people susceptible to certain serious diseases, is drawing on a network of pediatricians around the world to look for the relatively few young people who develop COVID-19 serious enough to get admitted to intensive care. "We study exclusively patients who were previously healthy" and under 50, as their serious COVID-19 illness is more likely to have a genetic basis, he explains.
In addition to genetic variants of the ACE2 receptor, scientists want to see whether differences in the human leukocyte antigen genes, which influence the immune system's response to viruses and bacteria, affect disease severity. And some investigators want to follow up a finding, which a Chinese team reported in a preprint: that people with type O blood may be protected from the virus. "We're trying to figure out if those findings are robust," says Stanford University human geneticist Manuel Rivas, who is contributing to Ganna's initiative.
The catastrophic spread of the coronavirus should soon increase the number of COVID-19 patients available to these gene hunts. And that could speed findings. Ganna expects the first susceptibility genes could be identified within a couple of months.
With reporting by Elizabeth Pennisi.