Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut.
Am J Med Genet B Neuropsychiatr Genet. 2014 Mar;165B(2):122-30. doi: 10.1002/ajmg.b.32221. Epub 2014 Jan 24.
Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high-throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community.
表型是与疾病相关的可测量生物标志物，至少部分是因为它们具有共同的潜在遗传影响。表型可以通过以下方式提高我们检测影响疾病风险的基因的能力：遗传上更简单，更接近基因作用的水平，遗传效应更大；或者通过其在诊断类别内对人的定量排序能力提供额外的统计能力。此外，它们还深入了解疾病的潜在机制，并将通过 RDoC 等努力在开发基于生物学的分类学方面发挥重要作用，RDoC 试图解释当前诊断类别内的异质性以及它们之间的重叠临床特征。虽然神经影像学、电生理学和认知测量目前在精神遗传学研究中应用最广泛，但研究人员目前正在尝试确定候选表型，这些表型的遗传复杂性较低，并且可能更接近基因作用的水平，如转录组和蛋白质组表型。筛选数以万计的此类测量需要自动、高通量的评估和潜在表型的排序方法，例如表型排名价值。然而，尽管表型在基因特征描述和发现方面具有潜在的效用，但精神科对表型方法存在相当大的抵制。在这篇综述中，我们解决并澄清了与精神遗传学领域使用表型相关的一些常见问题。
