In the early throes of the coronavirus pandemic, two brothers in the Netherlands fell sick with Covid-19. They were young — 29 and 32 — and previously healthy. But both brothers developed severe symptoms and, at the end of March, were admitted to the intensive care unit. Within days, the older brother couldn’t breathe on his own and needed ventilation. His younger brother came down with an unusually high fever and eventually died from complications of the disease.
A physician took note of the cases and contacted Alexander Hoischen, PhD, a geneticist at Radboud University Medical Center in Nijmegen, who set out to investigate why these brothers were so unusually affected. Sure, it could have been a coincidence, but Hoischen thought it was also possible that the brothers shared a genetic trait that compromised their immune systems.
“If you look at all the men hospitalized from Covid-19, it’s extremely unlikely that that happens to such young individuals, and then it happened twice in the same family,” Hoischen tells Elemental. “That was extremely remarkable to us.”
Days later, a second pair of brothers landed in separate Dutch hospitals. Both men, just 21 and 23 years old, also had difficulty breathing and were put on ventilators. CT scans revealed that the SARS-CoV-2 virus had ravaged the younger brother’s lungs. After more than a week in the hospital, both brothers were discharged. When Hoischen learned of the second pair of brothers, he was even more convinced that there was a genetic component to the young men’s severe disease.
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Over the course of the pandemic, it has become clear that certain factors — being elderly, male, obese, or a racial or ethnic minority — raise a person’s risk of developing severe Covid-19 and dying from it. Having an underlying chronic condition like diabetes, heart disease, or high blood pressure also significantly increases the likelihood of death. These factors can explain many cases of severe Covid-19 — but not all.
What’s so puzzling about the coronavirus is the wide spectrum of symptoms associated with it. Why do some people get a mild cough or no symptoms at all, while others go into respiratory failure? Why do many feel better within days, while others struggle to recover for weeks or months after infection? And why does a healthy person in his 20s succumb to a disease that spares the vast majority of people his age?
A person’s genetics could play a role. To learn more, scientists all over the world have been scanning huge genetic datasets, collecting DNA samples from Covid-19 patients, and analyzing their genomes in hopes of finding genetic signatures that explain why some people develop very serious symptoms.
Academic researchers and biotech companies have come together to form the Covid Human Genetic Effort and the Covid-19 Host Genetics Initiative, international consortiums that are pooling together data from thousands of patients in dozens of countries. Meanwhile, consumer genetics companies 23andMe and Ancestry are scouring DNA data from millions of customers to look for genetic links.
The results of these studies could help researchers develop new treatments or repurpose existing drugs to treat Covid-19 alongside other therapies. They could also lead to genetic tests that could predict someone’s Covid-19 risk. Genetic traits that predispose a person to more serious symptoms could even guide vaccine distribution. People with these traits could be prioritized for a vaccine, when one becomes available.
“It’s not unprecedented for people to have genetic differences that make them more or less susceptible to infection,” Catherine Ball, PhD, chief scientific officer at Ancestry, tells Elemental.
“There will most definitely be a genetic component associated with disease severity… However, the degree to which the impact is seen is yet to be determined.”
Perhaps the most well-known genetic trait associated with immunity is the sickle cell trait, which is most common in people from Africa or those of African descent. Carriers of sickle cell disease — those who have one sickle cell gene and one normal gene — are protected from malaria infection. But people who inherit two copies of the sickled gene from each parent develop sickle cell disease, a chronic and painful blood condition.
Another genetic trait with an effect on immunity is a specific mutation in the CCR5 gene. This subtle genetic change provides protection against HIV by blocking the virus from entering immune cells. Only about 1% of northern Europeans carry two copies of the mutation; one copy does not prevent infection.
Researchers have also identified single-gene mutations, known as inborn errors of immunity, that weaken the immune system. While some undermine the body’s ability to fight all infections, others may affect a person’s risk to a specific pathogen, like influenza or Epstein-Barr virus. Now, early research is revealing that a subset of people with severe Covid-19 harbor similar single-gene mutations that seem to have a big impact on the course of their disease. These mutations are likely rare in the general population. For others, a combination of several genetic variants and other risk factors, like preexisting conditions, may explain some extreme cases.
“There will most definitely be a genetic component associated with disease severity,” Joseph Petrosino, PhD, chair of molecular virology and microbiology at Baylor College of Medicine, tells Elemental. “However, the degree to which the impact is seen is yet to be determined.”
For the two pairs of brothers in the Netherlands, a single genetic mutation seems to be at the root of the men’s severe symptoms. Hoischen and his team discovered this by taking blood samples from all four men and sequencing their DNA, spelling out each person’s genetic code. The human genome contains about 30,000 genes, so to narrow down their search, Hoischen and one of his collaborators, PhD student Cas van der Made, looked mostly at genes involved in the human immune system. They were looking for a possible shared cause among the men.
Sure enough, they found what they were looking for.
The search revealed that all four of the men had mutations in a gene called TLR7, which belongs to a family of genes involved in recognizing foreign pathogens. The healthy version of this gene makes interferon, an immune protein the body releases to recognize invading viruses and other pathogens. But the faulty version carried by the four young men meant they couldn’t make enough of this essential protein.
The location of the TLR7 gene — on the X chromosome — may explain some sex differences in severe Covid-19 infection. Most people born male have an X and a Y chromosome, meaning they have only one copy of the TLR7 gene. If that gene is mutated, they have no way of compensating for it. In contrast, most people born female have two X sex chromosomes, so if they have a mutation in one copy of the TLR7 gene, the second, normal copy is usually enough to compensate.
“Too little TLR7, or virtually no TLR7, as shown in both of our families, is really bad for you in a situation of Covid infection,” van der Made says.
“There are relatively few people who get really severe Covid-19, so our hypothesis was that this small fraction of people are so severe because they’re genetically different from all the other people.”
Hoischen’s team published their findings in the Journal of the American Medical Association in July. A few other research groups have identified additional TRL7 variants in severe Covid-19 cases, he adds. The results are awaiting publication.
The Covid Human Genetic Effort has also found evidence that a lack of interferons can lead to severe infection. In one study of 659 people hospitalized with severe Covid-19, researchers found that about 3.5% had mutations in a set of 13 genes linked to a subclass of interferons known as type I interferons. A small subset of those people were missing a gene entirely.
“There are relatively few people who get really severe Covid-19, so our hypothesis was that this small fraction of people are so severe because they’re genetically different from all the other people,” first author Qian Zhang, MD, a research associate at the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University, tells Elemental.
The “genetically different” people identified in this study carried different mutations across the 13 genes studied, but all of these mutations were connected to severe disease.
In a second study from the Covid Human Genetic Effort, scientists made another striking observation: 10% of nearly 1,000 people with severe Covid-19 produce rogue antibodies called “autoantibodies,” which attack the immune system instead of the virus and block type I interferon from doing its job. The majority of those who had these autoantibodies — 95% — were men.
Though autoantibodies don’t seem uncommon in severe Covid-19 patients, they appear to be rare in the general population. Out of a random selection of 1,227 healthy people, the researchers found only four people who had them. The researchers think genetic mutations could be responsible for some patients’ autoantibodies, but they haven’t yet pinpointed the culprit genes.
The studies are the first from the Covid Human Genetic Effort, which is led by Jean-Laurent Casanova, MD, PhD, head of Rockefeller’s St. Giles Laboratory, along with Helen Su, MD, PhD, at the National Institute of Allergy and Infectious Diseases. Hundreds of hospitals and more than 50 genome-sequencing hubs around the world are involved in the effort.
The findings suggest that people who don’t make enough interferon could be treated with interferon drugs already on the market. Because there are different types of interferon, those with autoantibodies to one type of interferon may still benefit from treatment with another type. Clinical trials are currently underway to test these treatments on hospitalized Covid-19 patients.
“From our data, we think you really have to use it at an early time point, because interferon itself is like the first alarm in your body,” Zhang says, explaining that interferon will likely not have much of an effect if a person is already several days into a severe infection. “At that time, the treatment is probably not going to be as beneficial as if you treat the patients early on.”
In the early days of the pandemic, consumer testing firms 23andMe and Ancestry realized they had something valuable to contribute to Covid-19 research: troves of customer DNA data.
“It started to become obvious that some people get terribly, terribly sick and die and some people didn’t,” Ancestry’s Ball says. “That was a signal to all geneticists that there’s something going on, because that’s very unusual behavior for a pathogen. It’s more likely to be something about the human hosts that’s causing that different severity of symptoms.”
In April, Ancestry asked 600,000 of its members whether they had tested positive for Covid-19 and, if so, what their symptoms were like. 23andMe did the same with 750,000 customers.
Scientists at the companies then scanned millions of genetic markers — specific sequences of DNA — in customer DNA data looking for links to self-reported positive tests. After a first look at its data, 23andMe announced in June that blood type, which is determined by the ABO gene, might explain a person’s susceptibility to Covid-19. Blood type O, in particular, appeared protective against infection.
The same month, a study published in the New England Journal of Medicine showed that among more than 1,500 Italian and Spanish people with Covid-19, infections were more common among people with blood type A and least common among people with blood type O. That paper, combined with 23andMe’s initial findings, seemed to confirm an early paper on blood type by Chinese researchers. Other scientists, though, haven’t found meaningful associations between blood type and Covid-19 susceptibility.
Adam Auton, PhD, vice president of human genetics at 23andMe, thinks it’s good that scientists are debating this association. “It’s almost certainly true that no one group is going to be able to establish all of the answers for understanding the role of genetics in Covid-19 outcomes,” he says.
23andMe researchers, along with other groups, such as the Covid-19 Host Genetics Initiative, have also identified a stretch of genes on chromosome 3 associated with disease severity. This long gene segment comes from Neanderthals and is carried by around 50% of people in South Asia and around 16% of people in Europe.
Uncovering genetic links to severe Covid-19 could improve the management of hospitalized patients and aid in the development of new treatments.
One gene in this region might help control the expression of the ACE2 protein, which serves as SARS-CoV-2’s main entry point into human cells. 23andMe’s scientists hypothesize that mutations in this gene may make it easier for the virus to enter cells.
An Ancestry study validates many of 23andMe’s findings and also identified a region near a gene previously linked to flu infection that points to Covid-19 susceptibility — but only in men. It could explain why men are more vulnerable to Covid-19 and also suggests that SARS-CoV-2 and influenza may use a similar mechanism to enter and multiply in a person’s cells. Both companies’ studies have yet to be peer reviewed.
Uncovering genetic links to severe Covid-19 could improve the management of hospitalized patients and aid in the development of new treatments. Knowledge of these links would allow scientists to search through libraries of existing drugs for those that work on specific genes. These drugs could then be tested on human cells in the lab, as well as in animals, to learn whether they’re effective against Covid-19.
“By identifying genetic traits that are seemingly associated with disease severity, we may get a more complete mechanistic view of how the virus works,” Petrosino, of Baylor College, says. “New drugs and new therapies could rise from these types of studies.”
The findings could also inform the development of a genetic risk test for severe Covid-19, which could help triage patients when they are first admitted to the hospital. Taking genetics into account with other risk factors, like sex, age, and underlying conditions, doctors could better predict which patients will require limited resources like ventilators.
In the Netherlands, the findings from Hoischen and his team have led the Radboud University Medical Center to offer TLR7 screening for young male patients with severe Covid-19. The team has also been in contact with other university medical schools in the country to retrospectively test these patients. So far, no other cases of TLR7 mutations have been identified.
Screening hospitalized patients for autoantibodies could also identify those whose disease may take a turn for the worst.
One company, GoodCell, based in Waltham, Massachusetts, is developing a commercial genetic test to predict a person’s risk of Covid-19 severity. The medical diagnostics company is working with the New York Blood Center to compare blood samples from healthy people and those who had mild or severe Covid-19. The results of the study will guide the design of a genetic test, says Salvatore Viscomi, MD, the company’s chief medical officer.
“You get tested and you would know your overall risk for severe disease. Then you can make decisions based on that,” he tells Elemental. If the test indicates a high risk of severe disease, for instance, that person could self-isolate and take more precautions. Or if a family member was deemed high risk, relatives might be more careful around them. He declined to say when the test would be available.
Along with a Covid-19 risk score, the company plans to provide consumers with a report on how they can mitigate their risk of infection.
Until such a test is available, people should still take the usual precautions of wearing a mask, social distancing, and staying home as much as possible. People who have previously come down with severe cases of the flu may need to be extra cautious, Zhang says. In 2016, the Rockefeller group found that the same set of genes associated with severe Covid-19 are also involved in severe flu, as well as herpes simplex encephalitis, a rare neurological disorder caused by the herpes virus.
“For now, these people should just stay at home,” Zhang says, “and if there’s a vaccine available, they should be the first one to get it.” She adds that people who have had a severe viral infection in the past and develop symptoms of Covid-19 should go to the hospital immediately and tell their doctor about their previous infection.
While it’s becoming evident that a small number of people have genetic risk factors that put them at unusually high risk for severe Covid-19, it’s not yet known what all these findings tell us about the average person’s risk. A clearer picture could emerge over the coming months. In the longer term, when the current pandemic eventually subsides, the genetic insight gleaned from this coronavirus could help us better understand other infectious diseases.
“What we’re learning in medicine in general is that no two people are the same,” says Petrosino, adding that more personalized treatments could result in better outcomes for patients. “The first way into that is to look at the genome.”