It is among the lingering mysteries of COVID-19: Why do some people catch it while others – sometimes even sleeping in the same bed – escape without symptoms?
Some of the factors that explain these differences have long been clear: Older adults are more likely to fall seriously ill, particularly if they smoke, are obese, or have diabetes. People never exposed to the coronavirus won't get sick, of course, and exposure to a high concentration poses a higher risk for infection.
The virus itself matters, too. The delta variant seems to be more contagious than earlier ones.
Even two people who look the same on paper can have a different reaction to COVID-19. Young, previously healthy people have died or been seriously disabled; 90-year-olds in cancer treatment have survived infection.
The explanation, a study published Thursday suggests, may lie in their genetics.
"The human genome, and not only the viral genome, matters," Andrea Ganna, one of the lead authors of the study, said Wednesday at a news conference. "Clearly, there is a role of genetics in COVID severity … it's one of the many risk factors."
In younger people, less likely to have health problems that put them at higher risk, genetics may play an even bigger role, said Ganna, a group leader at the Finnish Institute for Molecular Medicine and an instructor at Harvard Medical School and Massachusetts General Hospital.
The study, led by the COVID-19 Host Genomics Initiative, confirms or newly identifies 13 genes that appear to play a role in susceptibility to infection or that affect the severity of illness.
Some of these make sense. One gene is involved in the response to respiratory infections.
Others have no obvious explanation. Blood type affects 9% to 12% of disease susceptibility, but researchers said they could not explain why. Of two people with the same exposure to the virus, the one with Type O blood will have slightly lower risk of getting infected. Yet blood type appeared to have no effect on severity of disease.
To be teased out is the cause and effect, said Dr. Michael Murray, a professor of genetics and director for Clinical Operations in the Center for Genomic Health at the Yale School of Medicine, who was not involved in the study. High body mass index might be a risk factor for COVID-19 because being severely overweight may make it harder to clear a virus, or the genetics contributing to weight gain may be the same genes contributing to more significant illness, he said.
These genetic effects have about as much influence on susceptibility and seriousness of infection as the effect of obesity or diabetes, Benjamin Neale, a statistical geneticist at the Broad Institute of Harvard and MIT, said at the news conference.
"DNA isn’t destiny but it can load the dice," his colleague Hamdi Mbarek, research partnership director of the Qatar Genome Program, which participated in the research, said via email. "This study is a big step towards understanding how many people may be playing with loaded dice when it comes to getting severely ill – or even having ‘long COVID’ – from the Delta variant, and future variants of the virus."
Identifying these influential genes isn't trivial. The study involved 50,000 patients across 25 countries. The list of contributing researchers runs for 29 pages.
"It's really very important to conduct these studies on a worldwide level, because that increases our chance of making the broadest and most general discoveries," said Mark Daly, another of the lead authors, who directs the Finnish Institute for Molecular Medicine at the University of Helsinki and is a professor of genetics at Harvard Medical School.
The data set has been expanded to include 125,000 people who had confirmed COVID-19 cases. The more information researchers have, the more precisely they can identify which genes are involved in making people more susceptible to COVID-19 and more likely to end up hospitalized.
Diversity is crucial, the researchers said. At least one of the genes wouldn't have been identified if the samples had included only Europeans and Americans, Daly and others said.
"COVID-19 isn’t going away," Mbarek said. "This is the biggest single genetic study in history of how people with slightly different DNA respond very differently to a virus. And because for the first time a study like this has involved genetic data from all parts of the world, that data will be more powerful in spotting the right genes to help develop treatments for severe COVID or long COVID."
In the larger dataset, which hasn't been published, the same researchers found 10 new locations in the human genome associated with infection or severe COVID-19.
These genetic findings might help identify promising drugs for treating COVID-19, Daly said. Drugs that act on these genes might be "repurposed" to treat COVID-19, or drugs in the pipeline might be identified as having promise against the disease, he said.
It is not feasible to analyze the genetics of COVID-19 patients to predict who is at most risk for severe disease, Ganna said.
In addition to expanding the database, Neale said he hopes to explore the interactions between human genetics and the genetics of the virus that causes COVID-19.
Most genetic data has explored the susceptibility to chronic infections, such as HIV, Murray said, but COVID-19 offers the possibility of better understanding the genetics of the response to short-lived infections.
It may be possible by the next pandemic to link someone's genetics to their risk for infection or poor outcome, he said.
"Each virus, because of its life cycle, will have different host factors that allow it to thrive or cause resistance," Murray said. This study "lays the groundwork for better understanding of how to get at these things more quickly next time, so they can be applied at the beginning of a pandemic, rather than these insights coming at what we hope is the tail end."
The next major focus for geneticists, he said, will be looking for insights into "long-haul COVID," in which symptoms linger.