ACMG Statements Highlight Ongoing Concerns around Polygenic Risk Scores

In March, the American College of Medical Genetics and Genomics (ACMG) professional practice and guidelines committee published a statement in Genetics in Medicine outlining general considerations for using polygenic risk scores, or PRSs, for which there are no clinical guidelines.¹

What Is a Polygenic Risk Score?

A polygenic risk score, or PRS, is a general estimate of a person’s potential risk of developing a particular condition based on genetic data analyses that take into account combinations of single-nucleotide variants from multiple genes. From Alzheimer’s to heart disease, as of May 2, 2023, the PGS Catalog contains more than 3,600 polygenic scores derived from algorithms that weigh several genetic and nongenetic factors, such as sex, age, family history, etc.²

According to the ACMG, although PRSs are now being widely used in health care, there are currently no clinical guidelines for their use. Because it is a combined estimate based on several variants, a PRS cannot provide a diagnosis—it can only provide relative risk, or the likelihood, of developing a disease.

To help healthcare providers understand the limitations of PRSs, the ACMG outlined eight key points to consider:

1. PRS test results do not provide a diagnosis, instead they provide a statistical prediction of increased clinical risk.
2. A low PRS does not rule out significant risk for the disease or condition in question.
3. If the risk prediction of a PRS is derived from a population that is different from the patient being tested, then the results may have a poor predictive value for the patient.
4. Isolated PRS testing is not the appropriate test for clinical scenarios in which monogenic etiology is known or suspected.
5. Before testing, a patient and provider should discuss the indications for the PRS test, and the patient should be informed how the PRS results will be used to guide medical management.
6. PRS-based medical management should be evidence-based; however, there is currently limited evidence to support the use of PRS to guide medical management.
7. Clinical follow-up for PRS should be consistent with best practices outlined by professional societies. Where evidence-based practice guidelines exist, they should be applied with appropriate expertise.
8. The ACMG’s position is that preimplantation PRS testing is not yet appropriate for clinical use and should not be offered at this time.³

Based on these eight points, the ACMG seems skeptical of PRS testing in general:

“At this time, the ACMG advocates against clinical implementation of PRS testing unless the provider and patient have a clear understanding of the limitations of the testing and applicability to the specific patient, including how the results will be used to guide evidence-based clinical care,” wrote the authors.

The ACMG also highlighted concerns around the data used to develop PRS algorithms. Historically, genetic studies have often focused on European-based data sets and have failed to include a diverse source of genetic data, leading to significant biases.⁴ This bias affects the accuracy of PRSs in people of non-European decent, contributing to ongoing healthcare disparities.

In April, the ACMG also published an accompanying statement recognizing the clinical, technical, and environmental biases in clinical genetic testing, “with the goal of fostering awareness and identifying strategies to reduce bias and improve health equity.”⁵

Moreover, evidence that demonstrates that PRS could lead to better clinical outcomes due to early intervention is limited, necessitating further studies, wrote the ACMG, which also called for more data on the cost-effectiveness of PRS assessment.

“Preimplantation PRS Testing Is Not Yet Appropriate for Clinical Use”

Though several US-based companies, such as Genomic Prediction, Orchid Health, and MyOme, are already exploring the use of PRS in preimplantation genetic testing, in point number 8, the ACMG clearly opposes using PRS to select embryos for implantation:

“Owing to the complexity of PRS testing and the interpretation and applicability of its results, the ACMG considers preimplantation genetic testing for disorders that exhibit multigenic or polygenic inheritance is not appropriate for clinical use and should not be offered as direct-to-consumer testing at this time.”

According to Patrick Turley, a professor of economics and director of the Behavioral and Health Genomics Center at the University of Southern California, who presented his research on this topic during the ACMG annual meeting in March, today’s parents who are considering testing their embryos and using that data to select which to implant simply do not understand the risks and limitations behind PRSs. Turley emphasized the disconnect between researchers and the science and the public’s knowledge of the subject.⁶

Considerations for Laboratories Implementing PRS Testing

The ACMG later published a statement of the laboratory’s perspective in the development and use of PRSs to help clinical laboratory geneticists provide quality genetic testing and reporting of PRS, including:⁷

1) general considerations for PRS-based genetic tests,

2) considerations for laboratories implementing PRS testing,

3) recommended criteria for reporting PRSs, and

4) defining and disclosing the scope and limitations of PRS testing.

In this statement directed at laboratories, the authors emphasized that “the limitations and uncertainties of PRSs should be clearly indicated in the report,” as well as “a general limitation statement detailing reduced performance in specific ethnicities or admixed populations,” among other recommendations.

References:

1. https://www.gimjournal.org/article/S1098-3600(23)00816-X/fulltext
2. https://www.pgscatalog.org/
3. https://www.nejm.org/doi/10.1056/NEJMsr2105065
4. https://www.nature.com/articles/s41588-019-0379-x
5. https://www.sciencedirect.com/science/article/pii/S1098360023008250
6. https://www.science.org/doi/10.1126/science.ade1083
7. https://www.sciencedirect.com/science/article/pii/S1098360023008171