Polygenic risk scores and the genetics of common diseases

Professor Gil McVean FRS, FMedSci, Founder & Chief Scientific Officer

The use of genetic information to identify people at greater risk of developing common diseases - ranging from heart disease to breast cancer - is well established in healthcare. Many health systems have programmes to identify people carrying rare mutations to enable more focused, personalised prevention and management to be offered. For example, for many women carrying BRCA gene mutations, steps can be taken to reduce the chances of developing advanced and life-threatening breast cancer - the NHS breast screening programme offers more frequent screening from a younger age, and some women choose to have preventative surgery. Similarly, there are forms of inherited heart disease that arise through mutations in familial hypercholesterolaemia (FH) genes. For carriers of such mutations, cholesterol-lowering treatments, such as statins, can offer effective prevention. 

In the last few years the importance of a different type of genetic risk - polygenic risk - has become evident. Polygenic risk - captured through a polygenic risk score (PRS) - captures the cumulative impact of large numbers of common variations in our DNA - small, simple variations that individually change risk only a little, but added together can greatly affect our risk. PRS represents a totally independent way of identifying individuals at increased risk of these common diseases. Critically, people with high PRS scores for FH and breast cancer have a similar risk profile, or likelihood of developing heart disease and breast cancer, as those people carrying high-risk mutations linked to these conditions. In many common diseases, people with a high PRS also account for more patients out of the total than those with high-risk mutations.

For example, women identified as carrying mutations in the BRCA1 or BRCA2 genes have a lifetime risk of breast cancer that exceeds 50%, several times higher than the 13% risk of the general population. In our recent paper we showed that the lifetime risk for carriers of BRCA mutations - roughly one in 250 women - is comparable to that of those women in the top 0.2% by their PRS. 

In fact, there are five ‘familial breast cancer genes’ that are routinely tested for mutations (ATM, CHEK2 and PALB2 in addition to BRCA1 and BRCA2). Roughly one in 75 women carries a mutation in at least one of these genes and has a lifetime risk comparable to the top 3% tested by polygenic risk score. Importantly, among women diagnosed with breast cancer before the age of 50 there are more than twice as many with high polygenic risk as those carrying mutations.

Similar patterns are seen for FH. Carriers of FH mutations - typically in the genes LDLR, APOB or PCSK9 - have up to a 20-fold greater risk of coronary artery disease compared to the average person. In our most recent paper analysing the performance of our PRS, we found that the top 8% of individuals with the highest PRS are at the same level risk of heart disease as carriers of mutations linked to FH. 

These results provide a compelling argument for equivalent care and treatment, such as statins or earlier and more frequent mammograms, to be offered to women and men with high genetic risk - whether that is due to the inheritance of specific mutations or through the inheritance of a much broader set of genetic risk factors that add up to a comparable risk.

Until now there has been no way to identify this latter group and they have been invisible to health systems and doctors, but PRS scores change that. We now have the tools to identify these people and to offer them the right care and management to try to prevent disease or catch it early.