Transethnic Transferability of a Genome-Wide Polygenic Score for Coronary Artery Disease

Genome-wide polygenic scores (GPSs) integrate information from millions of sites of common DNA variation into a single metric of inherited susceptibility. When applied to coronary artery disease (CAD), we and others have noted 3 key observations: (1) GPSCAD identifies a subgroup of the population at substantially increased risk not reliably identified using traditional risk factors; (2) GPSCAD can be quantified from birth, yet demonstrates similar or better discrimination power as clinical risk factors ascertained in middle age, and (3) individuals with high GPSCAD derive the greatest risk reduction from lipid-lowering therapy.1 Despite growing evidence for integration of polygenic scores into routine clinical practice, the Eurocentric bias in genome-wide association studies—needed as input to polygenic score derivation—results in reduced performance of most polygenic scores in non-European ancestries. To further quantify the transethnic portability of GPSCAD, we assembled a meta-analysis of 30 365 CAD cases and 482 063 controls across 5 ancestral groups derived from 6 studies. First, the UK Biobank, a cohort study of middle-aged individuals that included 22 250 cases and 441 490 controls. Second, 2 hospital-based biobanks in the United States, the Partners Biobank with 2772 cases and 15 124 controls, and the BioMe biobank with 2824 cases and 21 547 controls.2 Third, 2 ancestryspecific case-control studies, the BRAVE study (Bangladesh Risk of Acute Vascular Events) of early-onset myocardial infarction with 247 cases and 244 controls, and the TaiChi consortium in Taiwan with 288 cases and 457 controls.3,4 Fourth, 1984 cases with early-onset myocardial infarction from the hospital-based VIRGO study (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) and 3201 controls free of CAD from the MESA (Multi-Ethnic Study of Atherosclerosis) prospective cohort study.5 CAD was defined as myocardial infarction and history of coronary revascularization in all studies, with some variability across studies based on study design or available data as detailed previously.1–5 Participants within each study provided informed consent to study investigators, with the meta-analysis approved by the Mass General Brigham institutional review board. UK Biobank data are made available to qualified researchers via application (http://www.ukbiobank.ac.uk/register-apply). Data for the VIRGO, MESA, TaiChi, and BRAVE studies have been uploaded to the database of Genotypes and Phenotypes under accession numbers phs001259, phs001416, phs001487, and phs001398. Data from BioMe and Partners Biobank may be available via outreach to study investigators. To quantify the relationship of GPSCAD with disease, we first computed the GPSCAD in each study participant based on either genotyping array and imputation (UK Biobank, Partners Biobank, and BioMe) or whole-genome sequencing (TaiChi, BRAVE, and VIRGO/MESA). Sample and variant quality control were performed separately in each study as previously described.1,2,5 Ancestral subgroups were based on concordance between self-report and genetically defined ancestry, excluding individuals with discordant self-report and genetically SHANMUGA D