Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0126, USA.
Mol Psychiatry. 2010 Aug;15(8):789-97. doi: 10.1038/mp.2010.8. Epub 2010 Feb 9.
This paper provides a conceptual analysis of the endophenotype (EP) construct that is having an increasing role in genetic strategies for unraveling the etiology of psychiatric disorders (PDs). We make six major points illustrated through the method of path analysis. First, it is important to distinguish between mediational and liability-index (or 'risk indicator') models for EP, as only the former requires genetic risk for PD to pass through EP. Second, the relative reliability of EP and PD can have a critical role in the interpretation of results. Ignoring them can lead to substantial errors of inference. Third, we need to consider bidirectional relationships between an EP and a PD, and the possibility that genetic effects on PD are only partially mediated by EP. Fourth, EP models typically assume that all genetic effects that have an impact on EP also alter risk for PD. However, among the genetic influences on EP and PD, it is also plausible that some will influence only EP, some only PD and some both. Fifth, we should also consider models incorporating multiple EPs and PDs, which can be well captured by multivariate genetic methods. Sixth, EPs may also reflect the impact of the environment on risk for PDs. The EP concept has important potential lessons for etiological research in PDs that can be optimized by considering it as a special case of a broader set of multivariate genetic models, which can be fitted using currently available methodology.
本文对表型（EP）结构进行了概念分析，该结构在精神障碍（PD）病因学的遗传策略中发挥着越来越重要的作用。我们通过路径分析的方法提出了六点主要观点。首先，区分 EP 的中介和易感性指数（或“风险指标”）模型很重要，因为只有前者需要 PD 的遗传风险通过 EP。其次，EP 和 PD 的相对可靠性在解释结果时可以起到关键作用。忽略它们可能会导致推理的重大错误。第三，我们需要考虑 EP 和 PD 之间的双向关系，以及遗传对 PD 的影响可能仅部分通过 EP 来介导的可能性。第四，EP 模型通常假设对 EP 有影响的所有遗传效应也会改变 PD 的风险。然而，在 EP 和 PD 的遗传影响中，也有可能一些遗传效应仅影响 EP，一些仅影响 PD，还有一些同时影响两者。第五，我们还应该考虑纳入多个 EP 和 PD 的模型，这些模型可以通过多元遗传方法很好地捕捉。第六，EP 也可能反映环境对 PD 风险的影响。EP 概念为 PD 的病因学研究提供了重要的潜在经验教训，可以通过将其视为更广泛的多元遗传模型的特殊情况来优化，这些模型可以使用当前可用的方法来拟合。
