New DNA tests predict your disease risk – are we ready for them?

IT SOUNDS too good to be true: a medical test that can detect diseases you may develop decades from now. Suitably forewarned, you can take immediate steps to reduce your risk.

This is the promise of polygenic tests, so named because they involve sequencing multiple parts of someone’s DNA. They are being developed for a growing number of diseases, and advocates claim that they could revolutionise medicine by helping people avoid everything from type 1 diabetes to heart attacks and cancer. “If we can shift the focus to prevention, we could get a fundamentally different approach to healthcare,” says John Bell at the University of Oxford, who recently helped launch a massive pilot scheme in the UK involving the National Health Service.

It would be a big leap forward. Until now, we have only been able to predict someone’s risk of getting rare diseases caused by single genes. But soon we will be able to predict how likely you are to get the far more common conditions caused by multiple genes.

Yet some critics say this new era of preventive medicine is being rushed in without proper consideration of the consequences – for the people getting their risk scores and for healthcare systems. “These tests have benefits, but they also have risks and adverse events,” says Amit Sud at The Institute of Cancer Research in London.

What is clear is that with several polygenic risk tests already on sale to the public, we need to weigh up the costs and benefits from the impending uptake before it is too late.

Claims that genetics is about to transform medicine have been made since the start of the Human Genome Project. That research effort – a global, $3 billion collaboration to sequence all human DNA – produced a first draft in 2001. The then US president Bill Clinton said it would revolutionise the prevention and treatment of most, if not all, illnesses, and that his grandchildren might grow up in a world without cancer. “Humankind is on the verge of gaining immense new power to heal,” he said.

Since then, there have certainly been many genetics-based advances, but nearly all involve the small subset of conditions that stem from a mutation in one gene. Such “single-gene disorders” include cystic fibrosis, which causes lung damage, and haemophilia, the blood-clotting condition that can cause uncontrollable bleeding.

But single-gene disorders cause a small minority, perhaps just a few per cent, of illnesses. Everything else is governed by hundreds of variants in our DNA that each raise or lower the risk of an illness by a tiny amount – they are polygenic conditions. “It dawned on the community that we were looking at a very different genetic architecture,” says Michael Inouye at the University of Cambridge.

When we began to discover the polygenic nature of most human illnesses in the mid-2000s, it came as a blow. It would make it harder than we thought to develop drugs that block the effects of multiple genes at once. In addition, each gene variant tends to be rare, so finding them would require the DNA of huge numbers of people.

But as genetic analysis techniques advanced and costs fell, those larger studies began to be done, until they encompassed hundreds of thousands of people, in some cases millions. Complex equations were devised to turn the results of those hundreds of genetic variants into a single number for each condition, its polygenic score. A score can be turned into someone’s lifetime risk of developing a condition, which can be compared with the average figure for someone of the same age, sex and ethnicity.

At first, these equations were solely used in research. But as the price of DNA sequencing fell, there was nothing to stop firms like US personal genomics giant 23andMe adding polygenic scores to their single-gene health tests. 23andMe has offered a polygenic score for type 2 diabetes since 2019 and, in 2021, launched a package deal giving scores for 29 medical conditions or traits. Some US labs are also offering polygenic testing of embryos for in vitro fertilisation, so doctors can select the ones at lowest risk of certain conditions (see “Gene screening for embryos”, below).

Widespread polygenic testing

Until recently, the more tech-savvy could also upload their raw data from 23andMe or other firms into a free website called Impute.me, to get their scores for hundreds of different conditions or traits. Founder Lasse Folkersen says he started the site because some firms sell genetic tests that claim to provide useful medical information when, in fact, they only analyse no more than a few genes for each trait.

Impute.me went offline in 2022 after being bought by US company Nucleus Genomics, where Folkersen is now chief scientific officer. The firm plans to relaunch a commercial version of the technology.

In the UK, meanwhile, polygenic testing is about to become more widespread, as geneticists seek to harness the research potential of its National Health Service. A huge polygenic testing project called Our Future Health, which is planned to have 5 million participants, was launched in October. Its scale is unprecedented, recruiting about 1 in 10 adults in the UK, and its leaders have said they don’t plan to stop at 5 million. “The ambition is that we’ll just keep going,” says Bell.

While Our Future Health is billed as a research programme, it isn’t a randomised trial – it is more like a large-scale pilot to show up any practical problems with delivering the tests. It is as if the organisers have already decided that polygenic testing works, says Sud. “There’s a risk that we introduce something that we’re not able to step back from.”

Why might we want to step back? One issue is that polygenic scores are less accurate for people who aren’t white, because these people have typically been less likely to sign up for medical research. Our Future Health aims to correct this by recruiting more volunteers from non-white ethnic groups. Inouye welcomes that goal, but says it won’t necessarily be easy. “There are reasons why a lot of these people aren’t represented,” he says. “People from minorities and people who are not wealthy don’t necessarily have time to participate in a study, or they may feel taken advantage of by previous research.”

A more fundamental problem is that polygenic scores don’t usually provide much certainty. They are a measure of someone’s genetic risk of developing a particular condition – but the genetic contribution that we can identify so far for most medical conditions tends to be small. Environmental factors and chance events also influence someone’s risk of becoming ill, and those won’t show up on a polygenic score.

As such, the results of a polygenic test can confuse the recipient. This was illustrated in 2019, when the UK’s then health secretary, Matt Hancock, announced that he had learned his score for prostate cancer placed him at a higher risk – of 15 per cent by the time he reaches the age of 75. “This test may have saved my life,” said Hancock. But men’s average risk of the cancer is about 11 percent, so Hancock’s slightly higher figure makes little practical difference, scientists pointed out at the time. “This is difficult information to understand and process,” says Sud.

That doesn’t mean polygenic test results are always ambiguous. David Marshall was among the first users of 23andMe’s polygenic test for type 2 diabetes risk, and the company put New Scientist in touch with him to discuss his experience. The test placed Marshall at a 53 per cent risk of the condition, clearly higher than the average of 10 to 40 per cent for people of his age and ethnicity. But his experience illustrates another sticky issue. For many of the conditions at the forefront of polygenic testing, the advice for those at higher risk is the same as if they had never taken the test: avoid smoking, eat healthily, get some exercise.

Remember that the key claimed benefit of these tests is that they encourage people to take action that may help them avoid their predicted disease. Marshall says it worked for him: his genetic results helped motivate him to stick to a new healthy eating plan and start taking his dog out for extra walks. But research suggests that he is a rarity. For instance, one UK trial involving 569 people found that giving them either standard healthy lifestyle advice or combining it with their polygenic score for type 2 diabetes didn’t affect their subsequent diet or exercise levels. “Giving people information about their risk doesn’t make any difference to their habitual behaviours,” says Simon Griffin at the University of Cambridge, who helped run the study.

Of course, disease prevention doesn’t have to rely solely on people’s willpower to switch to a new healthier lifestyle. It could also involve taking cholesterol-reducing statins to prevent heart disease, for example, or having cancer-screening checks. If polygenic scores for cancer identify those at higher risk, they may be advised to have more frequent screening, such as breast checks, and to begin screening from a younger age. “Many women would see that as positive,” says Peter Donnelly at Genomics, a UK firm working with Our Future Health.

On the other hand, there are also downsides to cancer screening. Depending on the cancer type and age group, screening may do more harm than good. As screening providers acknowledge, it may find benign tumours that would never have got big enough to pose a risk to life. Surgery and chemotherapy to treat such tumours is not only costly, but also physically and emotionally draining.

In fact, a high polygenic score for any medical condition could, in theory, cause distress and anxiety – although the evidence for or against this idea is mixed. “Results from published studies have shown no long-term mental health impact of receiving genetic health results,” says a spokesperson for 23andMe. They pointed to a study suggesting no differences in rates of depression and anxiety in people getting results indicating they either did or didn’t carry a single gene predisposing them to a high risk for Alzheimer’s disease.

But another study, carried out on those using the Impute.me website, found that 61 per cent of users had some kind of a negative reaction after getting their results and 5 per cent met the criteria for potential post-traumatic stress disorder.

Revolutionising healthcare

Whether or not the tests cause anxiety, users are likely to seek further healthcare, ranging from a one-off doctor’s visit to discuss test results to seeking lifelong extra cancer checks – indeed, this is the desired outcome of the tests. For countries like England with a national health service, providers will need to weigh up whether such impacts are worth the uncertain benefits of the tests, especially if a new testing system is introduced suddenly, leading to a surge in demand that could overwhelm existing services. In places where medical care is funded by health insurance, this could lead to higher premiums, says Sud. “There are lots of unintended consequences.”

Folkersen says this still doesn’t justify restricting people’s access to information about themselves. Healthcare systems need to “rise to the challenge”, he says.

Donnelly says it would be short-sighted to judge polygenic testing by how it meshes with present-day health services. The ability to detect new disease risks may allow new kinds of prevention measures. One of the many traits his firm has developed polygenic scores for is age of menopause. Early menopause is linked with a younger onset of infertility, so anyone who finds out they are at risk of early menopause might want to start trying to have children sooner or freeze some of their eggs.

Another condition where prevention efforts could revolutionise healthcare is type 1 diabetes, which stems from a misplaced immune attack on pancreas cells that make the hormone insulin. The average age of onset is 13. An antibody treatment has recently been approved in the US that delays the immune attack by nearly three years, if given to children at risk because they have an affected relative. Refinements that lead to longer delays are in the works. Using polygenic scores could be one way to find more children who are at risk, says Kevan Herold at Yale University, who helped develop the antibody. “It may be time to consider screening the general population.”

Should polygenic risk scores therefore be prepared for babies, as soon as they are born? There are already trials running in several countries, including the UK, US and Australia, to sequence the entire genome of newborn babies to find rare, single-gene disorders that benefit from early diagnosis and treatment. There are concerns that these projects could make parents fearful about their children’s health. But doing polygenic testing takes things to the next level. We may reach a point where doctors tell families their children’s risks of all the most common medical conditions from birth. Nearly everyone could be given something to worry about.

There may be no single answer to whether polygenic scores are helpful or harmful – there will probably be differences depending on the medical condition involved and how easy it is to take any relevant preventive measures.

But Folkersen predicts that wider use of polygenic scores is on the way, regardless of any concerns now being raised. If health services don’t adopt them for official screening programmes, then private firms such as his will fill the gap. “People are very curious about themselves. Academics will discuss back and forth whether we should or should not have it, but what decides it is what normal people want,” he says. “It’s happening.”