Polygenic Risk Score Predicts Risk of Developing Common but Serious Diseases

Polygenic Risk Score Predicts Risk of Developing Common but Serious Diseases

by Dr. Lakshmi Venkataraman on Aug 14 2018 5:41 PM
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  • Polygenic risk scoring is a test developed to identify persons at increased risk of developing common but potentially serious diseases such as heart disease, type 2 diabetes, atrial fibrillation and cancer
  • Polygenic test identifies the sum of genetic alterations that are known to be associated with a specific condition such as heart disease or cancer and gives the risk score for that disease in an individual
  • Based on the risk score suitable treatments and preventive measures can be put in place much earlier to reduce the risk of the disease and its complications
Polygenic risk scoring test analyzes millions of sites in the human genome (entire set of human genes) to identify the occurrence of genetic alterations that have been shown to be associated with five common but potentially severe conditions namely coronary artery disease, diabetes, breast cancer, atrial fibrillation and inflammatory bowel disease.
Based on the combination of genetic alterations found in an individual he or she would then be assigned a risk score of developing that specific disease so that suitable preventive measures can be initiated earlier.

The study was conducted by scientists at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), and Harvard Medical School. The team included Sekar Kathiresan senior author who led the work with first authors Amit V. Khera, a cardiologist at MGH and junior faculty member in Kathiresan's lab, and Mark Chaffin, a computational biologist also in Kathiresan's lab.

The study findings have been published in Nature Genetics

According to senior author Sekar Kathiresan, an institute member and director of the Cardiovascular Disease Initiative at the Broad Institute, as well as director of the Center for Genomic Medicine at MGH and a professor of medicine at Harvard Medical School, "We've known for long time that there are people out there at high risk for disease based just on their overall genetic variation. Now, we're able to measure that risk using genomic data in a meaningful way. From a public health perspective, we need to identify these higher-risk segments of the population so we can provide appropriate care."


Identifying and Quantifying Risk of Developing Common but Serious Diseases

  • The study team first collected information from earlier genomic studies that have linked genetic alterations to specific diseases and identified various genetic variants associated with five common but potentially serious conditions like coronary artery disease, breast cancer, atrial fibrillation, type 2 diabetes and inflammatory bowel disease.
  • For each disease, they devised an algorithm (series of steps) combining information from all the known variants (most of which when present alone have little or no influence in increasing risk but do so in combination) that would calculate disease risk and give a single number, namely the polygenic risk score
  • Based on a person’s polygenic risk score for a particular disease, it is possible to predict the person’s chances of developing the disease later in life
  • The team validated the polygenic risk score algorithm by testing on data of over 400,000 individuals in the UK Biobank, an exhaustive database of genomic and clinical information from persons of British origin
  • Interestingly, persons with high polygenic risk score for heart disease did not show any warning signs or symptoms such as hypertension or high cholesterol, which are currently standard parameters that are measured to identify heart disease risk in the clinic. Thus it predicts risk much earlier even before patient shown has any symptoms.
  According to Khera, "These individuals, who are at several times the normal risk for having a heart attack just because of the additive effects of many variations, are mostly flying under the radar," he explained. "If they came into my clinical practice, I wouldn't be able to pick them out as high risk with our standard metrics. There's a real need to identify these cases so we can target screening and treatments more effectively, and this approach gives us a potential way forward."


Polygenic Risk Scores for Common Diseases in the Study

  • Among the volunteers in the UK Biobank dataset, 8 percent were more than thrice as likely to develop heart disease according to their risk score
  • Only 0.8 percent of individuals with very low polygenic risk scores had coronary artery disease, as opposed to 11 percent for the people with high polygenic risk scores
  • 1.5 percent of individuals in the UK Biobank database had more than triple the risk of developing breast cancer.
  • Persons with the highest polygenic risk scores had five times the risk of breast cancer; 19 percent of persons with top scores had breast cancer, as compared to about 4 percent of those with lower scores.
  • Similarly polygenic risk score for atrial fibrillation, type 2 diabetes and inflammatory bowel disease were obtained and validated
Thus the study suggests that a higher polygenic risk score is associated with an increased risk of developing the disease compared to a lower score in a given population


Scope of Study

If a disease is prevalent in a given population and has well-defined genetic associations, polygenic risk scoring could be incorporated in clinical practice to identify persons at risk . When this is followed by suitable

intervention measures and treatments much before symptoms appear, it can reduce the risk and improve the outcome for the patient.

Future Research in This Subject

  • Current study is based on data from persons of European descent; larger studies to include other racial groups are needed to widen the application of the polygenic risk screening to more populations
  • Similar research projects that gather data on genetic variants and disease associations and validating the results with reference biobanks are necessary to develop polygenic risk scores for more diseases
In conclusion, some day in the foreseeable future it may be possible to measure a person’s polygenic risk score to predict risk of getting a specific disease, much like we currently measure a person’s blood glucose or cholesterol.

  1. Amit V. Khera, Mark Chaffin, Krishna G. Aragam, Mary E. Haas, Carolina Roselli, Seung Hoan Choi, Pradeep Natarajan, Eric S. Lander, Steven A. Lubitz, Patrick T. Ellinor & Sekar Kathiresan., "Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations" (2018) Nature Genetics