The hope and hype surrounding polygenic risk scores

By Sowmiya Moorthie

20 March 2019


Health Secretary Matt Hancock has called for ‘game-changing’ predictive genetic testing for common diseases to be harnessed by the NHS to diagnose and prevent illness. Discussing his decision to undergo a predictive polygenic risk test for 16 common diseases, he described the news that the test identified him as having a 15% chance of developing prostate cancer as ‘not good news, but good news to have’.

Speaking at an event celebrating the 100,000 Genomes Project, he emphasised that predictive genomics is about risk factors, rather than absolutes, of which genes are only one part.

Personalising prevention

Diseases such as cardiovascular disease, diabetes and many cancers are leading causes of death and disability and place a huge burden on the NHS. Improved prevention of such conditions, which more personalised approaches such as polygenic risk scores may be able to offer, could have a significant impact on both individual and population health. Prevention of such conditions therefore forms an important theme in the Long Term Plan for the NHS.

Traditional health promotion measures such as smoking cessation programmes target large parts of the population and are known to be beneficial. Nevertheless, health systems are now looking to do more by designing prevention programmes that enable a more personalised approach to public health activities – precision public health.

A personalised approach is seen as an important component of preventative activities for common complex disorders and in ensuring healthier populations. Indeed, predictive prevention as envisioned by the Department of Health and Social Care, can be considered a part of this move towards precision public health. It aims to identify at-risk individuals at an earlier time-point and enable actions to reduce risk, including targeting interventions at those at greatest risk. This is becoming an increasing possibility with the development of mechanisms that identify those at risk and provide them with tailored interventions particularly through the use of digital technologies.

The role of genomics in predictive prevention

Genomics is recognised as a key component in achieving predictive prevention through enabling evaluation of disease predisposition and optimisation of preventative interventions. Genomic information is already used for this purpose in the management of the risk of cancer. With ground breaking initiatives such as the 100,000 Genomes Project, the new national NHS Genomic Medicine Service in England and Government plans to sequence up to five million individuals in the next few years, efforts to harness genomics for prevention of common diseases are gathering pace.

Science has made considerable progress in identifying common genetic variants/single nucleotide polymorphisms (SNPS) that are associated with many common diseases. Individually, each of these variants has a modest effect on disease risk, and so cannot meaningfully contribute to risk prediction. However, research has shown that taken together they can provide significant predictive ability, and this approach has been applied to several common diseases in the form of genetic or polygenic risk scores (PRS). SNPS are  attractive biomarkers as they are stable throughout the lifetime of an individual and hence could potentially provide information about disease predisposition at a very early time point.

Are we there yet?

The research community has demonstrated many potential applications of PRS for prevention of common complex disorders such as cardiovascular disease. Nevertheless, this is still an emerging field with many technical hurdles to overcome, including agreement of validated mechanisms to generate risk scores and ensuring a better understanding of the PRS-mediated risk across the life course and in the context of other risk factors. In addition, studies have not yet clearly demonstrated the clinical benefit of using PRS within healthcare.

As with many emerging technologies, the use of PRS within healthcare raises ethical, legal and social issues. A concern that has yet to be resolved is the applicability of currently available risk scores to non-Caucasian populations, as they have largely been developed based on genetic information from Caucasian populations. Other considerations include the best way to communicate risk and whether such large-scale sequencing would be acceptable to populations.  

We may not be there quite yet, but given the rate of developments in this field, it is likely that we will be soon - and clearly the Government is keen to harness the opportunities PRS may offer for improved prevention. At PHG Foundation we are already examining what developments in this field could mean for the NHS, building on our experience of genomics and personalised prevention.

What is clear is that the exact clinical application of PRS will differ substantially for diseases depending on the underlying genetic contribution of the disease, as well as current clinical and public health practice. Understanding which areas of clinical practice can benefit from developments in this fast-moving and complex field is the first step to realising its potential.

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