The landscape of genetic counselling is rapidly evolving, with polygenic risk scores (PRS) emerging as one of the most promising developments in personalized medicine. As we advance into 2025, the integration of PRS into clinical practice represents a paradigm shift from traditional single-gene testing to comprehensive genomic risk assessment. This transformation offers unprecedented opportunities to enhance patient care while presenting unique challenges that genetic counsellors must navigate.
Understanding Polygenic Risk Scores
Polygenic risk scores represent a revolutionary approach to genetic risk assessment that moves beyond the traditional focus on rare, high-penetrance variants to encompass the cumulative effect of thousands of common genetic variants. Unlike monogenic disorders where a single gene mutation determines disease risk, PRS captures the polygenic architecture of complex diseases by aggregating the small effects of multiple genetic variants across the genome.
The concept is elegantly simple yet computationally sophisticated. Each PRS is calculated by summing the number of risk alleles an individual carries, weighted by their effect sizes as determined from large-scale genome-wide association studies (GWAS). This numerical score provides a quantitative measure of genetic predisposition that can be compared to population averages and integrated with other clinical risk factors.
What distinguishes PRS from traditional genetic testing is their ability to provide risk information for virtually everyone, not just those with family histories or clinical presentations suggestive of monogenic disorders. This democratisation of genetic risk information has profound implications for population health screening and preventive medicine.
Clinical Evidence and Validation
The clinical evidence supporting PRS implementation has reached a critical mass in 2024, with particularly robust data emerging for cardiovascular disorders. In particular, 2024 saw considerable growth of evidence supporting the clinical utility of PRS for cardiovascular disorders such as coronary artery disease (CAD), especially when combined with other health-related data such as social determinants of health and lifestyle factors.
Recent studies have demonstrated that PRS can identify individuals at high genetic risk for coronary artery disease who would not be captured by traditional risk factors alone. These individuals may benefit from earlier interventions, more intensive screening, or lifestyle modifications that can significantly reduce their lifetime risk. The integration of PRS with established clinical risk calculators has shown improved discrimination and reclassification of patients into appropriate risk categories.
In oncology, breast cancer PRS have shown particular promise in clinical settings. Multivariate risk models are commonly used in clinical practice to estimate a woman’s lifetime risk for breast cancer and assist in implementation of appropriate screening and risk reduction strategies. More recently, breast cancer polygenic risk scores (PRS) have been derived and integrated into these models. Studies have demonstrated that breast cancer PRS can refine risk estimates provided by traditional models, potentially identifying women who would benefit from enhanced screening protocols or risk-reducing interventions.
The psychiatric applications of PRS are also gaining traction, though with more cautious implementation. PRS may thus one day contribute to personalized care in psychiatry. Polygenic risk scores (PRS) may aid in the identification of individuals at-risk for psychiatric disorders, treatment optimization, and increase in prognostic accuracy. PRS may also add significant value to genetic counselling.
Current Clinical Implementation Strategies
The transition of PRS from research laboratories to clinical practice requires careful consideration of implementation strategies. Polygenic scores (PGS) are primed for use in personalized risk assessments for common, complex conditions and population health screening. Although there is growing evidence supporting the clinical validity of these scores in certain diseases, presently, there is no consensus on best practices.
Healthcare systems are exploring various implementation models, ranging from targeted high-risk populations to broader population screening initiatives. The most successful implementations have focused on conditions with strong clinical evidence, established treatment pathways, and clear actionable interventions. For instance, cardiovascular PRS implementation has been most successful when integrated with existing cardiac risk assessment protocols and coupled with established prevention strategies.
The integration of PRS into electronic health records (EHR) systems represents a crucial implementation challenge. Successful programs have developed decision support tools that present PRS results alongside traditional risk factors, providing clinicians with comprehensive risk profiles that inform treatment decisions. These systems often include risk stratification algorithms that help identify patients who would benefit most from genetic counselling consultation.
Role of Genetic counsellors in PRS Implementation
Genetic counsellors are uniquely positioned to lead PRS implementation due to their expertise in risk communication, genomic interpretation, and patient counselling.
The genetic counsellor’s role in PRS implementation encompasses several key areas. First, they serve as interpreters of PRS results, translating complex statistical concepts into understandable risk information for patients and healthcare providers. This involves explaining concepts such as population percentiles, absolute versus relative risk, and the probabilistic nature of genetic risk prediction.
Second, genetic counsellors provide crucial context for PRS results by integrating them with family history, personal medical history, and lifestyle factors. This holistic approach ensures that patients receive comprehensive risk assessments that inform personalized prevention strategies. The counsellor’s expertise in risk perception and communication helps patients understand how their genetic risk translates into actionable health decisions.
Third, genetic counsellors play a vital role in addressing the ethical and social implications of PRS testing. They help patients understand the implications of genetic risk information for family members, insurance considerations, and psychological well-being. This counselling is particularly important given the population-wide applicability of PRS, which extends genetic risk information to individuals who may not have previously considered genetic testing.
Treatment Planning and Clinical Decision-Making
The integration of PRS into treatment planning represents a significant advancement in precision medicine. For cardiovascular disease, PRS can inform decisions about statin therapy initiation, blood pressure management intensity, and lifestyle intervention prioritisation. Patients with high PRS for coronary artery disease may benefit from earlier and more aggressive risk factor modification, even in the absence of traditional risk factors.
In oncology, PRS can refine breast cancer screening recommendations by identifying women who would benefit from enhanced screening protocols or risk-reducing interventions. Women with high breast cancer PRS may be candidates for earlier mammography screening, supplemental MRI screening, or discussions about risk-reducing medications or surgery. Conversely, women with low PRS may be reassured that standard screening protocols are appropriate.
The psychiatric applications of PRS in treatment planning are still emerging but show promise for treatment selection and dosing decisions. PRS may help identify patients who are more likely to respond to specific medications or who may be at higher risk for adverse drug reactions. This application requires careful consideration of the ethical implications of genetic testing for mental health conditions.
Challenges and Limitations
Despite the promising clinical evidence, PRS implementation faces significant challenges that genetic counsellors must navigate. The most pressing concern is the reduced predictive accuracy of PRS in diverse populations. Polygenic risk scores (PRSs) have shown promise for clinical implementation, but challenges remain, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients.
Most PRS have been developed using predominantly European ancestry populations, leading to reduced accuracy in African, Asian, Hispanic, and other non-European populations. This limitation raises serious equity concerns about the clinical implementation of PRS, as it may exacerbate existing health disparities. Genetic counsellors must be aware of these limitations and communicate them clearly to patients from diverse backgrounds.
The interpretation and communication of PRS results present additional challenges. Unlike traditional genetic testing that provides binary positive or negative results, PRS provide probabilistic risk information that can be difficult for patients and providers to understand. The continuous nature of PRS distributions means that most individuals will have intermediate risk scores, requiring nuanced counselling about risk implications.
Furthermore, the clinical utility of PRS depends heavily on the availability of effective interventions. For conditions where preventive strategies are limited or unclear, PRS may provide risk information without clear actionable steps. This situation requires careful consideration of the psychological impact of genetic risk information and the potential for patient anxiety or fatalism.
Ethical Considerations and Patient Autonomy
The implementation of PRS raises important ethical considerations that genetic counsellors must address. The population-wide applicability of PRS means that genetic risk information becomes relevant to virtually everyone, not just those with family histories of disease. This democratisation of genetic risk information challenges traditional models of genetic counselling that have focused on high-risk individuals.
Polygenic risk scores (PRS) are numerical indicators of risk based on multiple genetic markers associated with a disease or trait. The probabilistic nature of PRS results requires careful consideration of how risk information is communicated and used in clinical decision-making. Patients must understand that PRS provide risk estimates, not diagnostic certainties, and that environmental factors and lifestyle choices significantly influence disease development.
The potential for discrimination based on PRS results presents another ethical challenge. While current genetic non-discrimination laws may provide some protection, the widespread use of PRS could create new forms of genetic discrimination in insurance, employment, or other areas. Genetic counsellors must help patients understand these potential implications and make informed decisions about PRS testing.
Future Directions and Implications
The future of PRS in genetic counselling looks increasingly promising, with several developments on the horizon that will enhance their clinical utility. Ongoing research focuses on improving PRS accuracy in diverse populations through the inclusion of more representative datasets and the development of ancestry-specific scoring algorithms. These efforts are crucial for ensuring equitable access to precision medicine benefits.
The integration of PRS with other omics data, including transcriptomic, proteomic, and metabolomic information, promises to create more comprehensive risk prediction models. These multi-omics approaches may improve the accuracy of risk prediction and provide insights into disease mechanisms that inform treatment strategies.
The development of dynamic PRS that can be updated as new genetic discoveries emerge represents another promising direction. Unlike static genetic test results, these dynamic scores could provide increasingly accurate risk estimates as our understanding of disease genetics advances.
Conclusion
Polygenic risk scores represent a transformative development in genetic counselling, offering the potential to extend personalized medicine benefits to broader populations. Based on responses provided between October 2023 and January 2024, the growing genetic counselling workforce is well-positioned to lead PRS implementation and ensure that these powerful tools are used effectively and ethically.
The clinical evidence supporting PRS implementation continues to strengthen, particularly for cardiovascular disease and certain cancers. However, successful implementation requires careful attention to population diversity, clear communication of probabilistic risk information, and integration with existing clinical workflows. Genetic counsellors, with their unique expertise in risk communication and genomic interpretation, are essential leaders in this implementation process.
As we move forward, the key to successful PRS implementation lies in maintaining the core principles of genetic counselling: patient autonomy, non-directive counselling, and attention to the psychosocial implications of genetic information. By upholding these principles while embracing the opportunities presented by PRS, genetic counsellors can help realize the promise of precision medicine while protecting patient welfare and promoting health equity.
The journey from research tool to clinical reality is ongoing, but the evidence increasingly supports the transformative potential of polygenic risk scores in genetic counselling practice. As this field continues to evolve, genetic counsellors will play a crucial role in ensuring that these powerful tools are implemented thoughtfully, ethically, and effectively to improve patient outcomes and population health.
