PRS (polygenic risk score)

A polygenic risk score (PRS) is a single value that estimates an individual's genetic predisposition for a specific disease or trait by combining the effects of many common genetic variants.

Most common chronic diseases, such as coronary artery disease, type 2 diabetes, and schizophrenia, are not caused by a single faulty gene but are polygenic, meaning they arise from the cumulative impact of hundreds or even thousands of small genetic variations across the genome. A polygenic risk score seeks to quantify this combined genetic liability. It is calculated by analyzing an individual's DNA for specific genetic markers, typically single-nucleotide polymorphisms (SNPs), that have been associated with the disease in large-scale population studies known as Genome-Wide Association Studies (GWAS).

The calculation involves a weighted sum. Each SNP included in the score is assigned a weight based on the strength of its association with the disease. An individual's score is then computed by summing the weights of all the risk-associated variants they carry. The resulting score places the individual on a continuum of genetic risk relative to a reference population, often presented as a percentile. For example, a person in the 95th percentile has a higher genetic risk for the condition than 95% of the population.

Polygenic risk scores stand in contrast to the genetic testing used for monogenic (single-gene) disorders like cystic fibrosis or Huntington's disease. In monogenic diseases, a mutation in a single gene has a large and often deterministic effect on disease development. In contrast, a PRS provides a probabilistic, not deterministic, estimate of risk for complex diseases. It is a key tool in the field of precision medicine, which aims to tailor healthcare—including prevention, screening, and treatment—to the individual, taking into account their unique genetic, environmental, and lifestyle factors.

The primary significance of a PRS lies in its potential to improve disease prevention and early detection. By identifying individuals at high genetic risk long before any symptoms appear, clinicians could recommend targeted interventions. For instance, a person with a high PRS for coronary artery disease might be advised to adopt a stricter diet, begin an exercise regimen, or start preventative medication like statins at an earlier age. Similarly, a high PRS for breast cancer could inform decisions about the timing and frequency of mammography screening. However, it is crucial to recognize the limitations of PRS. The scores are not diagnostic; they only indicate predisposition, and a high score does not guarantee that a person will develop the disease. Furthermore, the predictive power of current scores is often modest and can be less accurate for individuals of non-European ancestry due to biases in the underlying research data. The clinical integration of PRS is an active area of research, focused on validating its utility and addressing these equity concerns.