Genetic risk scores developed for six diseases – Harvard Gazette

A team of researchers has developed a genetic risk score for six common diseases that can help doctors and patients make medical decisions.

A person’s risk of developing diseases such as type 2 diabetes or breast cancer can be affected by thousands of genetic differences. Looking at a single DNA difference that has a small effect on risk may not be clinically useful, but when hundreds or thousands of these small risks are added together into a single score, often called a polygenic risk score (PRS), they can offer clinically meaningful information about a person’s disease risk.

In a new paper published in Nature Medicine, researchers from Brigham and Women’s Hospital, Veterans Affairs Boston Healthcare System and Harvard Medical School developed and validated polygenic risk scores for six common diseases. The team also developed information resources for each disease to help physicians and patients discuss how to incorporate PRS when making medical decisions about screening and prevention.

“As a primary care physician myself, I knew that busy physicians would not have time to take a full course on polygenic risk scores,” said the corresponding author Jason Vassy of Brigham’s Division of General Internal Medicine & Primary Care, Brigham’s Precision Population Health at Ariadne Labs and VA Boston. “Instead, we wanted to design a laboratory report and information resources that briefly told the physician and patient what they need to know to make a decision to use a polygenic risk score in their healthcare.”

Vassy and colleagues developed the risk scores as part of the Genomic Medicine at VA (GenoVA) Study, a randomized clinical trial of PRS testing among generally healthy adults. The study team developed and validated a laboratory test at the Mass General Brigham Laboratory of Molecular Medicine (LMM) for polygenic risk score for atrial fibrillation, coronary artery disease, type 2 diabetes, breast cancer, colorectal cancer, and prostate cancer.

The GenoVA study currently enrolls patients at the VA Boston Healthcare System, and investigators reported the results of the first 227 patients, among whom 11 percent were found to have a high polygenic risk score for atrial fibrillation, 7 percent for coronary artery disease, 8 percent for type 2 diabetes and 6 percent for colon cancer. Among men, 15 percent had a high score for prostate cancer, while 13 percent of women had a high score for breast cancer. The GenoVA study will eventually enroll more than 1,000 patients and follow them for two years to observe how they and their primary caregivers use the polygenic risk scores in clinical care. For example, high-risk patients may choose to undergo screening tests more often or take preventative medications that may lower their risk.

The researchers had to address many challenges by implementing a clinical laboratory PRS test. Most importantly, their own observations confirmed a problem already known about these scores: they are less accurate in individuals of non-European descent. Most of the genomic research to date has been conducted in European populations, and the scores from this research therefore have a weaker ability to predict disease risk among non-European populations. Implementing a polygenic risk score in clinical care that is only accurate for people of European descent would exacerbate existing health inequalities. To address this important limitation, the researchers used additional statistical methods to enable PRS calculation across multiple racial groups.

“Researchers must continue to work to increase the diversity of patients participating in genomic research,” said Matthew Lebo, chief laboratory director at LMM. “Meanwhile, we were encouraged to see that we could generate and implement valid genetic scores for patients with different backgrounds.”

To date, 52 percent of GenoVA Study enrolled report non-white race and / or Hispanic / Latin ethnicity.

Another important challenge in bringing polygenic risk scores to clinical medicine is that physicians and patients will need support to understand them and use them to make medical decisions. There are no clinical guidelines yet to help a physician know if and how to treat a patient with a high-risk score other than an average-risk patient, but the study provides physician- and patient-oriented teaching materials to help them incorporate results. In addition, patients and primary care physicians may seek the support of a genetic counselor in the study.

The researchers hope that this first report from the GenoVA study will be a useful guide for other laboratories and healthcare systems looking to implement polygenic risk score testing in patient care. “It is still very early days for precision prevention,” says Vassy, ​​”but we have shown that it is possible to overcome some of the first barriers to bringing polygene risk scores into the clinic.”

Information: Vassy is employed in the U.S. Department of Veterans Affairs; the views expressed in this paper do not represent the views of the VA or the US Government.

This work was supported by the NIH National Human Genome Research Institute (R35HG010706) and NIH (R01HL139731, R01HL157635), American Heart Association (18SFRN34250007), National Heart, Lung and Blood Institute (R01HL142711, R01HL148050, R01L01H01H01H015H01 ), National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125782), Fondation Leducq (TNE-18CVD04) and Massachusetts General Hospital (Fire Chief).

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