If you or someone you know is considering genetic testing, you may encounter some new and unfamiliar terms. Most genetic tests ordered through a healthcare provider look for rare, or uncommon changes in your DNA (genetic variants) that may cause single-gene diseases. However, most diseases, such as most forms of cardiovascular disease, are caused by combinations of multiple genetic variants with environmental factors (e.g., smoking, diet).
The term “polygenic” refers to multiple genes, while “monogenic” refers to one gene. A polygenic risk score (PRS) is a measure used to gauge an individual’s risk for a complex disease. PRS compiles multiple common genetic changes into a single score to estimate how an individual’s risk for disease compares to others. When used in combination with other clinical and environmental factors, a PRS may provide patients with actionable steps to reduce their risk of developing particular diseases . However, as the PRS is a relatively new concept, in many cases, it needs to be improved before it can be widely used in clinical practice.
Origins of PRS
The idea of a PRS emerged in the late 2000s [2, 3], growing in popularity each year. A PRS can be a powerful tool to divide patients into groups of high, low, and normal risk for a specific condition. The scoring algorithms are based on genome-wide association studies (GWAS) that examine how frequently genetic variants are associated with traits. For example, a GWAS could examine patients with breast cancer and compare them to unaffected individuals to determine if a strong association with a particular genetic variant is present. Different genetic variants have different impacts on risk, so a PRS accounts for this by weighting more significant variants more heavily than less significant variants.
Current Clinical Use
The clinical utility of a PRS varies depending on the particular condition in question. At bare minimum, a PRS may provide an individual with an understanding of their risk of developing a particular condition and motivate them to take action to minimize this risk . For common metabolic diseases like Type 2 Diabetes (T2D) and cardiovascular disease, examples of these actions could include eating a balanced diet, exercising regularly, and quitting smoking. For more invasive interventions like drugs or surgical procedures, the PRS does not yet replace the knowledge of your healthcare provider with respect to what is best for your personal situation.
While an exciting innovation, the PRS is not without its limitations. The greatest limitation to the PRS is applicability of findings between diverse populations . Data from individuals with European ancestry have dominated the landscape of GWAS in recent years. For more information on how race and ethnicity affect genetic testing, see our blog post here.
PRS cannot rule out rare single-gene causes of disease. They have varying degrees of accuracy, and they don’t include every variant that may be associated with the disease. Furthermore, they can’t tell you your absolute risk of developing a specific disease. Instead, PRS estimates how your risk compares with other individuals with different risk scores. For example, the bell curve in Figure 1 below compares different levels of risk in the general population. For individuals scoring in the dark navy blue region to the right, additional disease risk mitigation efforts (diet, exercise, smoking cessation, therapeutics, etc.) may be appropriate. Notably, most individuals will fall in the gray region with low to average risk of developing disease.
Additional research, which is ongoing, will be needed to confirm the utility of PRS for more health conditions. Currently, the clinical use of PRS is frequently limited to cardiovascular disease and breast cancer, two well-funded and well-researched areas .
Genetic research improves each year with new information regarding complex health conditions. PRS, along with other metrics, may be a valuable future component of clinical care in that they allow an individual to better understand their personal genetic risks. If you have questions regarding whether a PRS can provide meaningful information to you or you need help interpreting the results of a test, please speak to your healthcare provider.
- Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 2007;17(10):1520-1528. doi:10.1101/gr.6665407
- International Schizophrenia Consortium, Purcell SM, Wray NR, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-752. doi:10.1038/nature08185
- Lewis, C.M., Vassos, E. Polygenic risk scores: from research tools to clinical instruments. Genome Med 12, 44 (2020). https://doi.org/10.1186/s13073-020-00742-5
- Duncan, L., Shen, H., Gelaye, B. et al. Analysis of polygenic risk score usage and performance in diverse human populations. Nat Commun 10, 3328 (2019). https://doi.org/10.1038/s41467-019-11112-0