Polygenic Risk Scores Perform Poorly in Screening and Predicting Common Diseases, Study Finds

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A new study finds that polygenic risk scores perform poorly in population screening, individual risk prediction, and population risk stratification, suggesting that polygenic risk score testing may not be as effective for disease screening and prevention as previously thought.

The study, published in BMJ Medicine, analyzed 926 polygenic risk scores for 310 diseases and found that, on average, only 11 percent of people who developed the disease were identified, while five percent of people had false positive predictions and did not go on to develop disease.       

"Strong claims have been made about the potential of polygenic risk scores in medicine, but our study shows that this is not justified,” said the study’s lead author, Aroon Hingorani, MD, PhD, of the University College London (UCL) Institute of Cardiovascular Science. "We found that, when held to the same standards as employed for other tests in medicine, polygenic risk scores performed poorly for prediction and screening across a range of common diseases."

According to the study, polygenic risk scores should not be confused with genetic testing for single-cell mutations such as BRCA1 and BRCA2, which have an established role in breast and ovarian cancer screening. Instead, polygenic risk scores estimate a person's disease risk based on thousands or millions of common genetic variants.

Researchers used data in an open-access database called the Polygenic Score Catalog to determine the detection and false positive rates of polygenic risk scores for disease screenings.

In the case of breast cancer and coronary artery disease, the risk scores successfully detected just 10 percent and 12 percent of eventual cases, respectively, with a threshold that led to five percent of individuals without the conditions testing positive.

Furthermore, they discovered that incorporating polygenic risk scores as an initial screening step to determine prioritization for mammography would overlook a significant number of women who subsequently develop breast cancer while producing a substantial number of false positives, exacerbating the strain on healthcare systems.

"Polygenic risk scores seem attractive because genotyping is now inexpensive, the same for all diseases, and is performed only once because a person's genotype does not change," said Jasmine Gratton, MD, of the UCL Institute of Cardiovascular Science and co-author of the study. "However, these features are irrelevant if the test is not useful."

According to the authors, these results add to growing evidence indicating that polygenic risk scores are not useful for public health screening programs. Still, they said research on variants associated with a higher disease risk remains crucial for drug development and understanding disease mechanisms.