18 Apr Brigham Researchers Develop Polygenic Risk Score Utilizing Diverse Genetic Databases
MedicalResearch.com Interview with:
Jason Vassy, MD, MPH
Brigham and Women’s Hospital
Division of General Internal Medicine & Primary Care
Brigham’s Precision Population Health at Ariadne Labs
and VA Boston
MedicalResearch.com: What is the background for this study?
Response: A person’s risk of developing diseases such as type 2 diabetes or breast cancer may be influenced by thousands of genetic differences, the effects of which can be combined to derive a single score, often called a polygenic risk score (PRS). PRS might be useful to help patients and their physicians make tailored decisions about their health care, but several challenges to the clinical implementation of PRS remain. Most importantly, most PRS are less accurate in individuals of non-European descent, since most genomic research to date has been conducted in European populations.
Another key challenge is that physicians and patients will need support to understand polygenic risk score and use them to make medical decisions. Clinical guidelines do not yet exist to help a physician know whether and how they should treat a patient with a high-risk score differently than an average-risk patient. We designed the Genomic Medicine at VA (GenoVA) Study to address some of these challenges.
MedicalResearch.com: What are the main findings?
Response: We chose six diseases that are commonly screened for or initially managed in primary care: atrial fibrillation, coronary artery disease, type 2 diabetes, colorectal cancer, breast cancer, and prostate cancer. We identified publicly available polygenic risk score for these diseases and then used data from the Mass General Brigham Biobank (MGBB) and other clinical samples to develop and clinically validate a laboratory assay for these six PRS. We initially observed that the scores performed less well in MGBB participants of self-reported Black and Asian race, so we applied additional statistical methods to correct for population structure, or systematic differences in the frequency of genetic variants that can confound the association between the PRS and the risk of disease.
We also developed a laboratory report to report the polygenic risk score to physicians and patients, along with informational materials to help them understand what the results mean. We are now using this laboratory assay in a clinical trial. Among the first 227 enrollees, 52% of whom report non-white race and/or Hispanic/Latinx ethnicity, more than 30% have a high-risk PRS for at least one of the diseases. The clinical trial is ongoing and will observe how patients and physicians use that information in medical decision-making.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The science underlying polygenic risk score is continually improving, most notably because of efforts to recruit increasingly diverse cohorts of people to genetic research and because of innovations in the statistical methods needed to improve the validity of PRS in diverse populations. These advances will be important for maximizing the accuracy of PRS for all people. As the clinical utility of polygenic risk score is defined, there will continue to be the implementation challenges that are always inherent to the introduction of a new technology to patient care. These include physician preparedness, EHR integration, and the proper place of PRS testing in patient care paths. Future work will need to define where, when, and how PRS testing fits into improving the way we take care of patients and the health outcomes they experience as a result.
Hao, L., Kraft, P., Berriz, G.F. et al. Development of a clinical polygenic risk score assay and reporting workflow. Nat Med (2022). https://doi.org/10.1038/s41591-022-01767-6
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