Thousands of genetic changes can influence a person’s likelihood of getting diseases like type 2 diabetes or breast cancer. A single DNA variant with a minor effect on risk may not be clinically relevant, but hundreds or thousands of these small risks combined into a single score, known as a polygenic risk score (PRS), may provide clinically useful information about a person’s illness risk.
Researchers from Brigham and Women’s Hospital, the Veterans Affairs Boston Healthcare System, and Harvard Medical School established and validated polygenic risk ratings for six major diseases in a recent report published in Nature Medicine.
The team also created instructional resources for each condition to assist physicians and patients in discussing how to incorporate PRS into screening and preventative decisions.
“As a primary care physician myself, I knew that busy physicians were not going to have time to take an entire course on polygenic risk scores,” said corresponding author Jason Vassy, MD, MPH, of the Brigham’s Division of General Internal Medicine & Primary Care, the Brigham’s Precision Population Health at Ariadne Labs and VA Boston.
“Instead, we wanted to design a lab report and informational resources that succinctly told the doctor and patient what they need to know to make a decision about using a polygenic risk score result in their health care.”
It produced the risk scores as part of the Genomic Medicine at VA (GenoVA) Study, a randomized clinical trial of PRS testing in otherwise healthy persons.
Researchers must continue working to increase the diversity of patients participating in genomics research. In the meantime, we were heartened to see that we could generate and implement valid genetic scores for patients of diverse backgrounds.Matthew Lebo
At the Mass General Brigham Laboratory for Molecular Medicine (LMM), the research team developed and validated a laboratory test for polygenic risk scores for atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer.
The GenoVA Study is currently enrolling patients at the VA Boston Healthcare System, and the researchers recently published the findings from the first 227 patients, of whom 11% had a high polygenic risk score for atrial fibrillation, 7% for coronary artery disease, 8% for type 2 diabetes, and 6% for colorectal cancer.
Prostate cancer got a high score among males (15%), whereas breast cancer had a high score among women (13%). More than 1,000 patients will be enrolled in the GenoVA Study, which will follow them for two years to see how they and their primary care physicians use polygenic risk scores in clinical care.
High-risk patients, for example, may elect to have more frequent screening tests or take preventive drugs to reduce their risk.
In order to establish a clinical laboratory PRS test, the researchers had to overcome numerous obstacles. Most crucially, their findings verified an issue with these scores that was already known: they are less accurate among people of non-European ancestry.
Because most genomic research has been done on European populations, the scores derived from this study are less effective at predicting illness risk in non-European populations.
Implementing a polygenic risk score into clinical care that is solely accurate for people of European heritage will worsen health inequities already present. To overcome this significant constraint, the researchers used additional statistical approaches to calculate PRS across a variety of racial groupings.
“Researchers must continue working to increase the diversity of patients participating in genomics research,” said Matthew Lebo, Ph.D., Chief Laboratory Director at the LMM. “In the meantime, we were heartened to see that we could generate and implement valid genetic scores for patients of diverse backgrounds.”
To date, 52 percent of GenoVA Study participants identify as non-white or Hispanic/Latinx.
Another significant obstacle in introducing polygenic risk scores into clinical medicine is that clinicians and patients will want assistance in comprehending and applying them to medical decisions.
Although no clinical guidelines exist to help a physician determine if and how to treat a patient with a high-risk score differently than a patient with an average-risk score, the study includes physician and patient-oriented teaching materials to help them apply the findings.
Patients and primary care providers can also seek help from a genetic counselor participating in the trial.
The GenoVA Study’s first report, the researcher’s hope, will serve as a useful reference for other laboratories and healthcare systems interested in implementing polygenic risk score testing in patient care.
“It’s still very early days for precision prevention,” says Vassy, “but we have shown it is feasible to overcome some of the first barriers to bringing polygenic risk scores into the clinic.”