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.

Download full-text


Available from: Michael C Neale
  • Source
    • "Second , the RDoC posits that variation in these functions improves our ability to identify biological mechanisms more than clinical symptoms can . However , such functions may turn out to be as complicated as symptoms or diagnoses ( Flint and Munafò , 2007 ; Kendler and Neale , 2010 ) . Third , the relationship between these functions and symptoms is weak at best ( Gold et al . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The grand challenges of schizophrenia research are linking the causes of the disorder to its symptoms and finding ways to overcome those symptoms. We argue that the field will be unable to address these challenges within psychiatry’s standard neo-Kraepelinian (DSM) perspective. At the same time the current corrective, based in molecular genetics and cognitive neuroscience, is also likely to flounder due to its neglect for psychiatry’s syndromal structure. We suggest adopting a new approach long used in reliability engineering, which also serves as a synthesis of these approaches. This approach, known as fault tree analysis, can be combined with extant neuroscientific data collection and computational modeling efforts to uncover the causal structures underlying the cognitive and affective failures in people with schizophrenia as well as other complex psychiatric phenomena. By making explicit how causes combine from basic faults to downstream failures, this approach makes affordances for 1) causes that are neither necessary nor sufficient in and of themselves, 2) within-diagnosis heterogeneity, and 3) between diagnosis co-morbidity.
    Preview · Article · Jan 2016 · Frontiers in Human Neuroscience
    • "As compared to complex personality traits such as extraversion and neuroticism and disease categories such as anxiety disorder and schizophrenia, the dimension of norm sensitivity is relatively unitary. Thus, it may be seen as an endophenotype, or intermediate trait, that links the operation of genes to actual behaviors[76]. Nevertheless, as should be clear from our discussion, the norm sensitivity itself could be divided into various component processes (e.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous research in cultural psychology shows that cultures vary in the social orientations of independence and interdependence. To date, however, little is known about how people may acquire such global patterns of cultural behavior or cultural norms. Nor is it clear what genetic mechanisms may underlie the acquisition of cultural norms. Here, we draw on recent evidence for certain genetic variability in the susceptibility to environmental influences and propose the norm sensitivity hypothesis, which holds that people acquire culture, and rules of cultural behaviors, through reinforcement-mediated social learning processes. One corollary of the hypothesis is that the degree of cultural acquisition should be influenced by polymorphic variants of genes involved in dopaminergic neural pathways, which have been widely implicated in reinforcement learning. We review initial evidence for these predictions and discuss challenges and directions for future research.
    No preview · Article · Dec 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2015 · Personality and Individual Differences
Show more