Ullah, Ehsan

Introduction: The potential use of polygenic risk scores (PRSs) in clinical practice is tempered by concern about their portability among diverse populations. To prevent disparities in genomic medicine, there is an urgent need to conduct genome-wide association studies in non-European ancestry cohorts. Methods: We conducted whole genome sequencing (WGS) with 30x coverage on coronary heart disease patients (n=1,067, mean age ± SD = 59.96 years ± 10.99; 70.32% males) and controls (n=6,170, mean age ± SD = 40.02 years ± 12.56; 43.45% males) in a Middle Eastern cohort to compare the performance of available PRSs for CHD (LDpred, metaGRS, lassosum, and P+T) and identify common variants associated with CHD (via generalized linear mixed models). Results: Excepting lassosum, all PRSs performed well. LDpred and metaGRS performed similarly (AUC= ~0.685) and outperformed P+T (AUC=0.667). Based on the OR per 1 SD increase (OR 1sd ), P+T (OR 1sd =1.85 [1.69-2.02], P =3.69x10 -41 ) outperformed other PRSs (OR 1sd =1.61 [1.48-1.74], P =3.02x10 -31 for LDpred and OR 1sd =1.61 [1.49-1.75], P =9.47x10 -31 for metaGRS). After binning PRSs into 10 deciles, the odds of CHD in the top decile compared to all others was highest for metaGRS (3.87 [3.07-4.88]) and LDpred (3.45 [2.74-4.341]). Thirty-two known GWAS loci (e.g., ABCG8 , CELSR2 , and SLC22A4 ) were replicated in our analysis with P <0.05. Seven suggestive new loci/genes ( P <10 -6 ) with relevant biological function were identified (e.g., CORO7 , RBM47 , and PDE4D ). The well-established 9p21 locus was not replicated. Conclusions: Genome-wide PRSs derived from European ancestry cohorts performed well in a Middle Eastern cohort. Further studies are needed to develop and validate an ancestry specific PRS and to confirm the suggestive loci/genes.