The Santander Biomedical Lectures program held a new session featuring Fernando Rivadeneira, Professor of Translational Genomics at Erasmus MC and an internationally recognized leader in genetics, clinical epidemiology, and musculoskeletal diseases, honored with distinctions such as the Fuller Albright Award. During his lecture, entitled “Clinical Applications of Polygenic Risk Scores,” he delivered a clear and rigorous presentation on how genomics is transforming risk assessment and opening new possibilities for truly personalized medicine.
Rivadeneira explained how polygenic risk scores (PRS) have been developed through genome-wide studies that, over the past two decades, have identified thousands of variants associated with different diseases. He noted that monogenic diseases, the most well-known, are caused by very rare mutations with a large effect. In contrast, in more common diseases, risk is driven by many frequent variants, each with a small effect, which together can significantly influence health. These accumulated variants form the basis of polygenic risk scores.
According to Rivadeneira, PRS combine these variants into a single score that allows estimation of an individual’s genetic predisposition. Their distribution in the population follows a normal curve, with small groups at the extremes concentrating significantly higher or lower risks. In certain cases, he emphasized, the cumulative effect can be comparable to that of a Mendelian mutation, reinforcing their clinical relevance.
From genetic prediction to clinical application
Rivadeneira described different approaches to calculating these scores—restricted, extended, and pathway-specific—and highlighted particularly the latter, which make it possible to identify the specific metabolic pathways contributing to risk. This approach enables more precise classification of complex diseases, which often group heterogeneous biological processes under a single diagnosis. As an example, he referred to type 2 diabetes, in which multiple organs and mechanisms are involved in its development, and where knowledge of a patient’s genetic profile can guide more specific preventive or therapeutic strategies.
In the field of osteoporosis, his main line of research, he showed how the combination of polygenic scores and Mendelian randomization studies makes it possible to identify truly causal factors—such as bone mineral density or muscle strength—and to rule out interventions with limited effectiveness, such as indiscriminate vitamin D and calcium supplementation in the absence of deficiency. He also emphasized their usefulness in anticipating potential adverse effects of new treatments and in integrating monogenic and polygenic genetic information into clinical practice.
The session highlighted that, although challenges remain in understanding the underlying biological mechanisms, polygenic risk scores represent a key tool for advancing toward a more predictive, preventive, and personalized precision medicine.
With this lecture, the Santander Biomedical Lectures program reaffirms its commitment to disseminating high-impact scientific advances and to promoting evidence-based precision medicine grounded in genetic research, aimed at improving the prevention, diagnosis, and treatment of complex diseases.
