Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia.
Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Herston QLD 4006, Australia.
Hum Mol Genet. 2020 Oct 20;29(R2):R165-R176. doi: 10.1093/hmg/ddaa136.
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.
遗传检测广泛应用于单基因疾病的诊断、携带者和预测性检测。直到最近，对于心脏病、糖尿病和癌症等多因素复杂疾病，还没有遗传检测的选择。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）方面非常有价值。对于给定的疾病，可以将 SNPs 组合起来，生成称为多基因风险评分（PRS）的风险累积估计。经过多年的研究，PRS 越来越多地在临床环境中使用。在本文中，我们将回顾有关全基因组和受限 PRS 如何开发以及每种方法的相对优点的文献。还将讨论 PRS 的验证和评估，包括认识到 PRS 的有效性与基础 GWAS 的方法学和分析方法以及该队列的种族特征内在相关。具体而言，人群差异可能会影响推断准确性、风险幅度和方向。即使 PRS 正在被引入临床实践，也有人推动将其与临床和人口统计学风险因素结合起来，以开发整体疾病风险。考虑了 PRS 在四个不同领域的临床实用性的现有证据：告知人群筛查计划、指导治疗干预、为高风险家庭细化风险、促进诊断和预测预后结果。总结了与五个研究充分的疾病有关的临床实用性证据。还强调了潜在的伦理、法律和社会影响。
