- Researchers at Massachusetts General Hospital previously calculated polygenic scores for coronary artery disease (CAD), atrial fibrillation, diabetes and severe obesity (BMI ≥40 kg/m2)
- In this study, using data on relatives from the UK Biobank, correlations of polygenic scores for CAD were r=1.0 (perfect) between 179 pairs of monozygotic twins and r=0.51 between 22,644 sibling pairs; similar results were observed for the other diseases
- When a high polygenic score was defined as the top 20% of the distribution—corresponding to a more than doubling of risk for each of the four diseases—about 45% of siblings similarly met that threshold
- When an individual proves to have a high polygenic score for a cardiometabolic disease, cascade testing to identify additional family members with a high score may be warranted
Polygenic scores integrate information from many common DNA variants into a single measure and quantify an individual's inherited risk of a given disease. Now Amit V. Khera, MD, MSc, cardiologist, a researcher in the Center for Genomic Medicine, and medical director of the Preventive Genomics Clinic at Massachusetts General Hospital, and colleagues have characterized what a high polygenic score means for the individual's family members. Their findings are published as a research letter in Circulation: Genomic and Precision Medicine.
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Correlations Between Relatives
The researchers previously calculated polygenic scores for coronary artery disease (CAD), atrial fibrillation (AF), diabetes and severe obesity (BMI ≥40 kg/m2). Using data on relatives from the UK Biobank, they found that for CAD, correlations of polygenic scores were:
- r=1.0 (perfect) between 179 pairs of monozygotic twins
- r=0.51 between 22,644 sibling pairs
- r=0.25 between 11,123 pairs of second-degree relatives
Nearly identical results were observed across the other diseases.
Predictive Value of a High Score
There is no standard for what a "high" polygenic score is, so the team explored multiple thresholds, including the top 1% and top 20% of the disease-specific distributions (the latter represents more than doubling of the risk):
- CAD—For individuals with a polygenic score in the top 1%, 21% of siblings' polygenic scores met the same threshold; for those in the top 20%, 44% of siblings' scores met the same threshold
- AF—15% and 46%, respectively
- Diabetes—12% and 44%, respectively
- Severe obesity—13% and 44%, respectively
The positive predictive value of a high polygenic score was largely independent of family history.
Disease discordance between sibling pairs was observed for:
- CAD—1,844 pairs
- AF—1,430 pairs
- Diabetes—2,376 pairs
- Severe obesity—749 pairs
The higher polygenic score was observed in the affected sibling in 1,071 (58%) of the pairs with discordant CAD status, significantly higher than the 50% that would be observed by chance (P<0.001). The pattern was similar across the three other diseases: 60% of pairs for AF, 60% for diabetes, and 67% for severe obesity.
Implications for Genetic Counseling
When an individual proves to have a high polygenic score for cardiometabolic disease, cascade testing to identify additional family members with a high score may be warranted. Individuals with high inherited risk may benefit from targeted screening for the disease and preventive interventions.
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