Clinical relevance of genome-wide polygenic score may be less than claimed
Clinical relevance of genome-wide polygenic score may be less than claimed
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DOI：
10.1111/ahg.12302
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发表时间：
2019-07-01
影响因子：
1.9
通讯作者：
Curtis, David
中科院分区：
文献类型：
--
作者：
Curtis, David
目的最近的一项研究声称，五种常见疾病的全基因组多基因评分（GPSs）可以识别具有相当于单基因突变风险的个体。据报道，受试者操作曲线分析的曲线下面积（AUC）范围从炎症性肠病的0.63到冠状动脉疾病（CAD）的0.81，但这些模型还包括年龄和性别，它们本身是风险的强预测因子。CAD的GPS确定了8%的人群的风险增加了三倍，据称这与单基因突变的过度风险相当。方法在本研究中，试图建立CAD的GPS分布模型，以匹配所提供的信息。这些模型的基础上报告的百分位数的GPS和GPS的分布在控制和情况下的流行率分布，并拟合报告的结果，使用线性近似的分布和使用模拟的责任阈值模型。结果不可能产生一个兼容的模型，其中GPS产生的AUC高达0.81，最合理的估计是真实的AUC仅为0.65。病例组和对照组中报告的GPS分布重叠太多，以至于它们与0.7或更高的AUC不相容。结论GPS对这些疾病的AUC是适度的。此外，文献有力地表明，与单基因突变相关的真正CAD风险远高于GPS预测的三倍增加。总之，这些发现对GPS的临床实用性提出了质疑。
Objectives A recent study claimed that genome-wide polygenic scores (GPSs) for five common diseases could identify individuals with risk equivalent to monogenic mutations. Receiver operator curve analyses were reported to have areas under the curve (AUCs) ranging from 0.63 for inflammatory bowel disease up to 0.81 for coronary artery disease (CAD), but these models also included age and sex, themselves strong predictors of risk. The GPS for CAD identified 8% of the population at threefold increased risk, which was claimed to be comparable to the excess risk from monogenic mutations. Methods In the present study, attempts were made to model the distribution of the GPS for CAD to match the information provided. These models were based on the reported distribution of prevalence by centile of GPS and on the distribution of GPS in controls and cases, and were fitted to the reported results using linear approximations to the distributions and using simulations of a liability-threshold model. Results It was impossible to produce a compatible model in which the GPS produced an AUC as high as 0.81 and the most plausible estimate was that the true AUC was only 0.65. The reported distributions of the GPS in cases and controls overlap so much that they are not compatible with an AUC of 0.7 or higher. Conclusions The AUC of the GPS for these diseases is modest. Furthermore, the literature robustly demonstrates that the true CAD risk associated with monogenic mutations is much higher than the threefold increase that is predicted by the GPS. Together, these findings cast doubt on the clinical utility of the GPS.