Transferability of published coronary artery disease and hypertension polygenic scores in a Kazakh cohort with ischemic heart disease and co-occurring arterial hypertension

Abstract Objective Polygenic scores may show variable transferability in populations underrepresented in their development datasets. We evaluated four published polygenic scores for coronary artery disease/coronary heart disease and hypertension in a Kazakh case-control cohort with ischemic heart disease and co-occurring arterial hypertension (IHD-HTN), and explored technical and population-genetic factors that might contribute to differences in score transferability. Results The analysis included 470 ethnic Kazakh individuals (240 IHD-HTN cases and 230 controls). Three of four scores were associated with IHD-HTN after adjustment for age, sex and ten genetic principal components, but only PGS005144 remained significant after correction for multiple testing (OR per 1 SD = 1.33, 95% CI 1.10–1.62). PGS003018 showed no association (OR = 1.01, 95% CI 0.84–1.23). Among the 100 highest-weighted variants, 90 were retained for PGS005144 versus 73 for PGS003018, representing 91.4% and 75.4% of summed absolute effect weight. Allele-frequency and local LD analyses did not support a simple East Asian-versus-European explanation. The clearest difference was poorer recovery of highly weighted PGS003018 variants after imputation and quality control. Internal validation did not show clear improvement in discrimination from adding the PRS.