Escott-Price Valentina, Hardy John
Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK.
Brain Commun. 2022 May 17;4(3):fcac125. doi: 10.1093/braincomms/fcac125. eCollection 2022.
As the size of genome-wide association studies increase, the number of associated trait loci identified inevitably increase. One welcomes this if it allows the better delineation of the pathways to disease and increases the accuracy of genetic prediction of disease risk through polygenic risk score analysis. However, there are several problems in the continuing increase in the genome-wide analysis of 'Alzheimer's disease'. In this review, we have systematically assessed the history of Alzheimer's disease genome-wide association studies, including their sample sizes, age and selection/assessment criteria of cases and controls and heritability explained by these disease genome-wide association studies. We observe that nearly all earlier disease genome-wide association studies are now part of all current disease genome-wide association studies. In addition, the latest disease genome-wide association studies include (i) only a small fraction (∼10%) of clinically screened controls, substituting for them population-based samples which are systematically younger than cases, and (ii) around 50% of Alzheimer's disease cases are in fact 'proxy dementia cases'. As a consequence, the more genes the field finds, the less the heritability they explain. We highlight potential caveats this situation creates and discuss some of the consequences occurring when translating the newest Alzheimer's disease genome-wide association study results into basic research and/or clinical practice.
随着全基因组关联研究规模的扩大，所识别出的相关性状位点数量必然会增加。如果这能更好地描绘疾病发生途径，并通过多基因风险评分分析提高疾病风险基因预测的准确性，那自然是值得欢迎的。然而，“阿尔茨海默病”全基因组分析的持续增加存在若干问题。在本综述中，我们系统评估了阿尔茨海默病全基因组关联研究的历程，包括其样本量、病例与对照的年龄以及选择/评估标准，还有这些疾病全基因组关联研究所解释的遗传力。我们发现，几乎所有早期的疾病全基因组关联研究现在都是当前所有疾病全基因组关联研究的一部分。此外，最新的疾病全基因组关联研究存在以下情况：（i）仅纳入了一小部分（约10%）经过临床筛查的对照，用系统性地比病例年轻的基于人群的样本替代了它们；（ii）约50%的阿尔茨海默病病例实际上是“代理痴呆病例”。因此，该领域发现的基因越多，它们所解释的遗传力就越低。我们强调了这种情况带来的潜在问题，并讨论了将最新的阿尔茨海默病全基因组关联研究结果转化为基础研究和/或临床实践时所产生的一些后果。
