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

Abstract

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 studies for coronary heart disease in a Middle Eastern cohort using whole genome sequencing and assessed the performance of 6 existing PRSs developed with methods such as 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 1sd ) was highest for PGS000337 (OR 1sd =1.81, 95% CI [1.66–1.98], P =3.07×10 −41 ). EnsemblePRS performed better than individual PRSs (OR 1sd =1.8, 95% CI [1.66–1.96], P =5.89×10 −44 ). 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 association studies loci, 33 replicated at P <10 −4 . However, the 9p21 locus did not replicate. Six suggestive ( P <10 −5 ) new loci/genes with plausible biological function were identified (eg, CORO7 , RBM47 , and PDE4D ). The burden of rare functional variants in LDLR , APOB , PCSK9 , and ANGPTL4 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.

Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

“…It will be important to validate them in an independent Middle Eastern cohort with welldefined cases and controls and to develop ancestry-specific PRSs. Recently, several PRSs for coronary heart disease were validated in a Middle Eastern cohort [31]. To improve equitable genetic risk prediction for diverse populations, collecting more well-defined and large disease cohorts are needed.…”

Identification of a NovelSLC2A9Gene Association with LDL-C levels and Evaluation of Polygenic Scores in a Multi-Ancestry Genome Wide Association Study

“…PGS development for predicting LDL-C levels or CVD within the wider Middle Eastern region based on local genomic variation has not been systematically explored. A recent study on a cohort of coronary heart disease (CHD) from Qatar showed that performance of PGS derived from European studies of CVD was comparable to the performance reported in Europeans (21).…”

Pragmatic Approach to Applying Polygenic Risk Scores to Diverse Populations

“…Readers can then decide where they fall on the spectrum for each step based on unique aspects of their population and datasets available at their disposal. For example, in the case of an indigenous Arab population, where datasets are limited but environmental risk factors are unique, it might be necessary to borrow effect estimates from global GWAS studies (Saad et al., 2022). In South Asian or East Asian populations where there are emerging larger datasets, using population‐specific GWAS to update effect size estimates might be feasible (Koyama et al., 2020; Weissbrod et al., 2022).…”