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首页> 外文期刊>Circulation. Genomic and precision medicine. >Validation of Polygenic Risk Scores for Coronary Heart Disease in a Middle Eastern Cohort Using Whole Genome Sequencing
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Validation of Polygenic Risk Scores for Coronary Heart Disease in a Middle Eastern Cohort Using Whole Genome Sequencing

机译：使用全基因组测序验证中东队列中冠心病的多基因风险评分

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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 30x 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 (OR1sd) was highest for PGS000337 (OR1sd=1.81, 95% CI [1.66-1.98], P=3.07x10~(-41)). EnsemblePRS performed better than individual PRSs (OR1sd1sd=1.8, 95%CI [1.66-1.96], P=5.89x 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 significant loci, 33 replicated at P<10~(-4). However, the 9p21 locus did not replicate. Six suggestive (P<10~(-6)) new loci/genes with plausible biological function were identified (eg, CORO7, RBM47, 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.
机译：背景:利用多基因风险的热情分数(prs)在临床实践中就会受到影响关注不同的可移植性祖先群体,从而激励全基因组相关研究在非欧洲血统军团。协会为冠心病研究中东队列使用全基因组测序和评估6 prs的性能开发方法包括中将(PGS000296) metaGRS (PGS000018),修剪阈值(PGS000337),和一个EnsemblePRS我们发展。脂质基因在病例和罕见变异控制。在1067年进行冠心病吗例(平均年龄= 59年;控件(平均年龄= 40年;男性)。好,最高PGS000337 (OR1sd = 1.81, 95%可信区间表现好于单独的prs10 ~(-44))。剩余PGS000337十分位数> 3.2,PGS000296 PGS000018,达到4.58EnsemblePRS。位点,33 P < 10 ~(4)复制。9 p21轨迹没有复制。(P < 10 ~(6))新位点/基因与似是而非的生物功能被确定(如CORO7,RBM47 PDE4D)。LDLR,变体飞机观测、PCSK9 ANGPTL4的情况下比控制。总的来说,我们证明prs来自欧洲血统的全基因组关联研究在中东群,表现良好表明这些能否应用于临床设置而ancestry-specific prs发展。

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