Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.

中文翻译：

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多基因风险评分的新兴领域和用于临床护理的前景。

基因检测广泛用于单基因疾病的诊断、携带者和预测性检测。直到最近，还没有可用于心脏病、糖尿病和癌症等多因素复杂疾病的基因检测选项。全基因组关联研究 (GWAS) 在鉴定与数百种复杂疾病的风险增加或降低相关的单核苷酸多态性 (SNP) 方面非常宝贵。对于给定的疾病，可以组合 SNP 以生成称为多基因风险评分 (PRS) 的累积风险估计。经过多年的研究，PRS 越来越多地用于临床环境。在本文中，我们将回顾有关如何开发全基因组 PRS 和限制性 PRS 以及各自的相对优点的文献。还将讨论 PRS 的验证和评估，包括认识到 PRS 有效性与基金会 GWAS 的方法论和分析方法以及该队列的种族特征有着内在联系。具体而言，人口差异可能会影响插补准确性、风险大小和方向。即使在将 PRS 引入临床实践时，也有人推动将它们与临床和人口统计学风险因素结合起来，以形成整体疾病风险。关于 PRS 临床效用的现有证据在四个不同领域进行考虑：告知人群筛查计划、指导治疗干预、改善高危家庭的风险以及促进诊断和预测预后结果。总结了与五种经过充分研究的疾病相关的临床效用证据。