Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization

作者：Johanna L. Smith, Catherine Tcheandjieu, Ozan Dikilitas, Kruthika Iyer, Kazuo Miyazawa, Austin T. Hilliard, Julie A. Lynch, Jerome I. Rotter, Yii‐Der Ida Chen, Wayne Huey‐Herng Sheu, Kyong‐Mi Chang, Stavroula Kanoni, Philip S. Tsao, Kaoru Ito, Matthew Kosel, Shoa L. Clarke, Daniel J. Schaid, Themistocles L. Assimes, Iftikhar J. Kullo · 发表于：Circulation Genomic and Precision Medicine · 年份：2024 · DOI：10.1161/circgen.123.004272 · 被引用次数：39 · 研究领域：Genetic Associations and Epidemiology、Liver Disease Diagnosis and Treatment、Folate and B Vitamins Research

BACKGROUND: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRS CHD ) for 5 genetic ancestry groups. METHODS: We derived ancestry-specific and multi-ancestry PRS CHD based on pruning and thresholding (PRS PT ) and ancestry-based continuous shrinkage priors (PRS CSx ) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRS CHD in 176,988 individuals across 9 diverse cohorts. RESULTS: Multi-ancestry PRS PT and PRS CSx outperformed ancestry-specific PRS PT and PRS CSx across a range of tuning values. Two best-performing multi-ancestry PRS CHD (ie, PRS PTmult and PRS CSxmult ) and 1 ancestry-specific (PRS CSxEUR ) were taken forward for validation. PRS PTmult demonstrated the strongest association with CHD in individuals of South Asian ancestry and European ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41–3.14], 1.65 [1.59–1.72]), followed by East Asian ancestry (1.56 [1.50–1.61]), Hispanic/Latino ancestry (1.38 [1.24–1.54]), and African ancestry (1.16 [1.11–1.21]). PRS CSxmult showed the strongest associations in South Asian ancestry (2.67 [2.38–3.00]) and European ancestry (1.65 [1.59–1.71]), lower in East Asian ances...