Population-wide risk scores limited ability to predict disease

Testing a population for multiple genes at once will only have limited ability to accurately predict disease risk, according to a new paper.

Strong claims have been made about the transformative potential of using what are called polygenic risk scores to predict, prevent and detect disease and such testing has attracted the interest of policy makers and the commercial sector.

However, in an analysis article in the British Medical Journal, clinical researchers from UCL, The Institute of Cancer Research, London, and the University of Oxford argue that the predictive performance of such tests is limited. 

Co-author Professor Aroon Hingorani (UCL Institute of Cardiovascular Science), who is also Cardiovascular Theme Lead for the UCLH NIHR Biomedical Research Centre and a Consultant in Internal Medicine at UCLH, said: “Population-wide ‘polygenic scoring’ is inherently limited because many cases of disease occur among people who do not have high polygenic scores and many of those with high polygenic scores do not develop disease.”

The authors argue that the risks and benefits of genetic testing must be carefully evaluated in large studies. Their analysis concludes that initiatives which use polygenic scores to screen for people at risk of common illnesses such as cancer and heart disease will miss most cases in the population.

When screening the population for a disease using polygenic scores, many have advocated for using a high polygenic score to target screening or preventative strategies for disease. According to the researchers doing so would miss most of the disease in the population and result in a sizeable number of healthy individuals undergoing invasive tests and therapies who will never go on to develop the disease.

For example, NICE uses a 17 per cent lifetime risk of breast cancer as the threshold for deeming women at ‘moderate risk’. But in a polygenic risk score study which also used this threshold, only 39 per cent of women who will go on to develop breast cancer have moderate or high-risk scores, meaning the majority of breast cancer cases are missed using these scores. Meanwhile, 22 per cent of women who will not develop breast cancer will have a high polygenic risk score and will therefore be a ‘false positive’.

More about polygenic risk scoring

DNA sequence commonly varies between individuals at many different points throughout the genome. Some of these genetic variants influence individual risk of common diseases such as dementia, cancer, diabetes, and cardiovascular disease, through effects on the expression or function of the encoded proteins. The effects of these variants on disease risk in any individual can be summarised by generating a polygenic risk score.

NHS genetic testing currently focuses on a small number of well-understood disease mutations which strongly raise the risk of disease – such as BRCA1 and BRCA2 in breast and ovarian cancer.

Polygenic scoring is a different type of genetic test which instead looks across thousands of common variants in a person’s DNA, each of which will individually have only a small impact on risk, to gain a collective assessment of the genetic risk of disease.