A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.

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Patel, Aniruddh P 
Ruan, Yunfeng 
Koyama, Satoshi 

Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.


Funder: Massachusetts General Hospital (MGH); doi: https://doi.org/10.13039/100005294

Funder: Broad Institute; doi: https://doi.org/10.13039/100013114

Funder: Harvard Catalyst (Harvard Clinical and Translational Science Center); doi: https://doi.org/10.13039/100007299

Humans, Coronary Artery Disease, Genome-Wide Association Study, Genetic Predisposition to Disease, Risk Factors, Phenotype
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Nat Med
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Springer Science and Business Media LLC
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RE/18/1/34212)
British Heart Foundation (RG/18/13/33946)
National Institute for Health and Care Research (IS-BRC-1215-20014)