Ancestry-Based Disparities in Cardiovascular Outcomes and Polygenic Risk Among Adults with Congenital Heart Disease in the All of Us Research Program

Most individuals born with congenital heart disease now survive to adulthood, producing a growing population at risk for major adverse cardiovascular events (MACE). Ancestry-based disparities are incompletely characterized and polygenic risk has not been related to outcomes. We analyzed 6,771 adult ACHD participants in All of Us (White n=5,065, Hispanic n=882, Black n=824) and computed five polygenic scores: one for coronary artery disease and four for heart failure trained on African, European, Hispanic or Latin American, and multi-ancestry data. MACE was present in 51.0% and differed by ancestry (Black 56.3%, White 50.7%, Hispanic 47.5%; P=0.001). Black participants developed heart failure 11 years earlier (median 54 vs. 65 years). The pooled disparity attenuated to the null after comorbidity adjustment, with chronic kidney disease accounting for 58.6% of the age- and sex-adjusted effect, but age-specific estimates opposed one another (adjusted OR 1.78 at 40, 0.66 at 80; interaction P<0.001); survivor selection may contribute at older ages. No score improved discrimination or explained the disparity (area under the curve change ≤0.0047). The African-ancestry score was associated with heart failure alone (OR 1.09 per SD, q=0.022); the European and multi-ancestry scores with heart failure, arrhythmia, and MACE alike. Performance did not track training-population ancestry. The coronary and African-ancestry scores ordered the same participants in opposite directions (r=–0.198), indicating between-group offsets reflect allele frequency rather than genomic risk. Black participants underwent fewer structural cardiac reinterventions (8.6% vs. 16.4%; adjusted OR 0.47, P<0.001) despite comparable adjusted ACE inhibitor or angiotensin receptor blocker prescription.