Endophenotype: a conceptual analysis. Mol Psychiatry

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0126, USA.
Molecular Psychiatry (Impact Factor: 14.5). 02/2010; 15(8):789-97. DOI: 10.1038/mp.2010.8
Source: PubMed


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.

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    • "Specific and rigidly held dysfunctional beliefs could be promising candidate endophenotypes, particularly if considering research using the OBQ (Taylor, 2012). Dysfunctional beliefs as measured by the OBQ fulfill several criteria to be candidate endophenotypes (as they are currently conceptualized) (Cannon & Keller, 2006; Kendler & Neale, 2010) for OCD. In fact 1) OBQ scores are correlated with the severity of OC symptoms and are higher in people with OCD compared to clinical and non-clinical controls; 2) dysfunctional beliefs appear to be causes rather than consequences of OCD; and 3) twin studies show that dysfunctional beliefs and OC symptoms arise, in part, from a shared set of environmental and genetic influences. "
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    ABSTRACT: Background: Specific dysfunctional beliefs have been identified as candidate endophenotypes for Obsessive-Compulsive Disorder (OCD). Rector et al. (2009) investigated cognitive vulnerability for OCD and their results support both the notion of familial-based origin of obsessive beliefs, and the hypothesis that inflated responsibility/overestimation of threat, could represent candidate endophenotypes for OCD. Aims: The primary aim of this study was to replicate previous findings of a familial cognitive vulnerability for OCD. The secondary purpose was to test the hypothesis that obsessive beliefs of patients with OCD and those of their first-degree relatives (FDRs) are correlated, supporting dysfunctional beliefs as candidate endophenotypes for OCD. Method: 65 patients with DSM-IV-TR (SCID-I) OCD were included together with one healthy FDR. 77 non-affected FDRs of patients with Bipolar Disorder were enrolled as a control group. Obsessive beliefs were measured with the OBQ-44. Results: First-degree relatives of subjects with OCD scored significantly higher than controls on the total score and on the domain tapping inflated responsibility and overestimation of threat. There was no significant correlation between each obsessive belief in patients with OCD and their non-affected FDRs. Conclusions: Our study provides evidence of a specific cognitive vulnerability for OCD in FDRs of probands with OCD.
    Personality and Individual Differences 12/2015; 87. DOI:10.1016/j.paid.2015.07.047 · 1.95 Impact Factor
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    • "The effect of genes on depression is generally small (see meta-analysis of López–León et al., 2007). Intermediate phenotypes represent heritable phenotypic constructs, which are presumably more directly related to genetic variations than disease symptoms and hence may allow more powerful genetic analyses (Franke et al., 2009; Gottesman and Gould, 2003; Hasler et al., 2004; Kendler and Neale, 2010). To illustrate, the 5-HTTLPR polymorphism S allele was associated with negative memory bias in never-depressed children (Hayden et al., 2008). "
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    ABSTRACT: The tendency to recall more negative and less positive information has been frequently related to the genetic susceptibility to depression. This memory bias may be associated with depression candidate genes especially in individuals who experienced stressful childhood events. The serotonin transporter gene, SLC6A4/5-HTT, regulates the reuptake of serotonin. The 5-HTTLPR polymorphism in the gene's promoter region has a short (S) and a long (L) allele, of which L contains a further SNP (rs25531), resulting in a triallelic polymorphism: La, Lg, and S. Both S and Lg result in increased serotonin signaling (to simplify, we refer to both alleles as 'S'), which in turn appears associated with depression vulnerability, specifically in individuals with stressful events. In non-depressed individuals (N=1083), we examined the interaction between the 5-HTTLPR genotype (LaLa, SLa, and SS) and stressful childhood events in association with explicit verbal memory bias (positive, negative). Two types of stressful childhood events were studied, namely childhood adverse events (e.g. parental loss) and interpersonal traumatic childhood events (e.g. abuse). Less positive memory bias was found for individuals with the SS genotype who had experienced interpersonal childhood traumatic events. No general association of genotype with memory bias was found, nor was there a significant interaction between genotype and childhood adverse events. Our results suggest that the depression-susceptibility genotype of the 5-HTTLPR is associated with depressive information processing styles when occurring in combination with traumatic childhood events. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising. Copyright © 2015 Elsevier B.V. All rights reserved.
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    • "Depression is a complex multifactorial condition with considerable heritability, but genetic studies so far have yielded mixed findings (Sullivan et al., 2000). A potential way to increase the power to detect genetic effects is to investigate the information-processing tendencies of depression (Gottesman and Gould, 2003; Kendler and Neale, 2010). Currently, depressed patients show better memory for negative than for positive information (Matt et al., 1992; Ridout et al., 2003; Mathews and MacLeod, 2005; Gotlib and Joormann, 2010). "
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