This summer, a small group of researchers at the Roslin Institute, University of Edinburgh, began to notice something unusual. They were looking at the DNA of thousands of people who had contracted Covid-19 and suffered severely – people who were touch-and-go in intensive care units, some who survived and some who didn’t.
The researchers were comparing these genetic profiles to those of people with similar backgrounds held in the UK BioBank, which holds information on half a million volunteers. The aim was to see if anything stood out in those who had been brought to the brink by Covid.
Why do some people shrug off Covid with barely a cough, while others were brought low and, all too often, killed by it. Of course, some risk factors quickly became plain: age, obesity, ethnicity, diabetes. But the team wanted to know something else. Were some victims potentially being condemned by their genes?
“On average there are between four and five million genetic differences between two people,” says Dr Kenneth Baillie, the critical care doctor leading the study, to which The Telegraph has been given exclusive access. Pinpointing the handful that might exacerbate Covid seemed an almost impossible task.
But painstaking work gradually began to weed out those that were not relevant. As August moved into September, “a signal began to emerge through the noise”. Five locations on the human genome stood out.
Still, it was not enough to be sure. So the team went back and compared their patients against genetic profiles in another biobank – Generation Scotland – then England’s 100,000 Genomes Project, to see if the same variations emerged again. They did.
“It was incredibly exciting,” says Baillie, of the groundbreaking findings which were presented in a paper published in Nature on Friday. “Today, what we’re sure about is that five points on the human genome are definitely associated with becoming critically ill if you have Covid. And it is particularly exciting because we know what those genes do.”
Of the five, one was known about, a region on chromosome 3, one of the 23 pairs of chromosomes in the human genome. In June, a team published research in the New England Journal of Medicine, identifying a cluster of half a dozen genes affecting immune response – a response that, if it gets out of hand, can lead to death.
The Edinburgh team, however, revealed four other genetic clues. The first, on chromosome 12, is a cluster of three genes – OAS1, 2, and 3 – which are critical to the body mustering and deploying its defences, notably by preventing the virus reproducing. A variant in the OAS gene cluster, present in 63 per cent of us, could hamper that process, allowing the virus to replicate more easily. Those with it are 1.3 times more likely to develop a critical case of Covid.
The second gene – IFNAR2 – was found on chromosome 21. It builds cell receptors for molecules called interferons – proteins named for their ability to foil viral reproduction, but some 28 per cent of UK volunteers of European genetic ancestry have a variant of this gene which, again, leaves them 1.3 times more likely to become severely ill. For Baillie, the two findings were entirely logical. “They are so intimately associated with defence against viruses,” he said. “But the others are teaching us new things.”
Those surprises came with the identification of a gene called TYK2, on chromosome 19, a variant of which can stimulate dangerous inflammation in the lungs, a critical element of late-stage, life threatening Covid-19.
The fourth discovery, also on chromosome 19, was DPP9. “It’s known to be associated with lung fibrosis,” says Bailie, referring to scarring caused in the healing process. “Like TYK2, it is associated with immune responses that cause inflammation.”