Endophenotype: a conceptual analysis

Abstract

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.

Figure 1

(a) A liability-index model for endophenotypes (EPs). Genetic variance V_G influences both an EP and a psychiatric disorder (PD). These observed variables also have residual variation, RVEP and RVPD, due to other sources. (b) A mediational model for EPs. Genetic variance causes variation in the EP, which in turn causes variation in PD. EP and PD have residual variance components RVEP and RVPD, respectively.

Figure 2

(a) A mediational model for endophenotypes (EPs) including errors of measurement. The residual variance components of EP and psychiatric disorder (PD) are partitioned into reliable and measurement error variance. (b) A liability-index model for EPs including errors of measurement. The residual variance components of EP and PD are partitioned into reliable and measurement error variance. (c) A liability-index model for EPs including two assessments at different times and errors of measurement.

Figure 3

A nonexclusive mediational model for endophenotypes (EPs) including a direct causal path from genes to the psychiatric disorder (a_PD) that does not pass through EP.

Figure 4

(a) A bivariate model for genetic risk factors for an endophenotype (EP) and a psychiatric disorder (PD). The correlation between them is represented by r_g. (b) A conceptual bivariate model for genetic risk factors for an EP and a PD. One biological pathway splits into two, with one path leading to EP and the other to PD. Genetic factors may influence each of the steps of the pathway.

Figure 5

A model incorporating three genetic risk factors, two endophenotypes and one psychiatric disorder. Residual variation, specific to each of these three phenotypes, is shown as RVEP1, RVEP2 and RVPD.

Figure 6

A model incorporating one set each of genetic and environmental risk factors, three endophenotypes and one psychiatric disorder. Residual variation (RV) components are shown for all four phenotypes.