Validation of Polygenic Risk Scores for Coronary Heart Disease in a Middle Eastern Cohort Using Whole Genome Sequencing.

Background: Enthusiasm for using polygenic risk scores (PRSs) in clinical practice is tempered by concerns about their portability to diverse ancestry groups, thus motivating genome-wide association studies in non-European ancestry cohorts.

Methods: We conducted a genome-wide association study for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 PRSs developed with methods including LDpred (PGS000296), metaGRS (PGS000018), Pruning and Thresholding (PGS000337), and an EnsemblePRS we developed. Additionally, we evaluated the burden of rare variants in lipid genes in cases and controls. Whole genome sequencing at 30× coverage was performed in 1067 coronary heart disease cases (mean age=59 years; 70.3% males) and 6170 controls (mean age=40 years; 43.5% males).

Results: The majority of PRSs performed well; odds ratio (OR) per 1 SD increase (OR) was highest for PGS000337 (OR=1.81, 95% CI [1.66-1.98], =3.07×10). EnsemblePRS performed better than individual PRSs (OR=1.8, 95% CI [1.66-1.96], =5.89×10). The OR for the 10th decile versus the remaining deciles was >3.2 for PGS000337, PGS000296, PGS000018, and reached 4.58 for EnsemblePRS. Of 400 known genome-wide significant loci, 33 replicated at <10. However, the 9p21 locus did not replicate. Six suggestive (<10) new loci/genes with plausible biological function were identified (eg, , , ). The burden of rare functional variants in , , , and was greater in cases than controls.

Conclusions: Overall, we demonstrate that PRSs derived from European ancestry genome-wide association studies performed well in a Middle Eastern cohort, suggesting these could be used in the clinical setting while ancestry-specific PRSs are developed.