The Genetic Deconstruction of Psychosis

Department of Psychological Medicine, The School of Medicine, Cardiff University, Cardiff, UK.
Schizophrenia Bulletin (Impact Factor: 8.45). 08/2007; 33(4):905-11. DOI: 10.1093/schbul/sbm053
Source: PubMed


Psychiatric research, including the search for predisposing genes, has tended to proceed under the assumptions that schizophrenia and bipolar disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and International Statistical Classification of Diseases, 10th Revision, are discrete disease entities with distinct etiology and pathogenesis and that these disease entities can be identified by current "operational" diagnostic conventions. However, recent findings emerging from genetic studies show increasing evidence for an overlap in genetic susceptibility across the traditional binary classification of psychosis. Moreover, the emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, variation in Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional categorical approach. We can expect that, over the coming years, molecular genetics will catalyze a reappraisal of psychiatric nosology as well as contribute in a major way to our understanding of pathophysiology and to the development of improved treatments. However, our understanding of the brain mechanisms that link specific gene actions and products to the subjective experience of psychopathological symptoms is likely to be bridged by employing intermediate (or endo-) phenotypes in the domains such as cognition, neurophysiology, or neuroanatomy rather than relying upon clinical measures alone.

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    • "This is consistent with the glutamatergic hypothesis, which posits that NMDAR hypofunction contributes directly to negative symptoms and neurocognitive dysfunction and to positive dysfunction via the dysregulation of dopamine [10]. The D-amino acid oxidase activator gene (DAOA) and the regulator of G-protein signalling 4 gene (RGS4) have been considered candidate genes because their encoded proteins play a role in regulating glutamatergic neurotransmission, and it is therefore hypothesized that they contribute to the genetic liability continuum described between psychotic disorders [11]. DAOA (13q33.2) encodes the protein DAOA, which activates Damino acid oxidase (DAAO) in the brain, an enzyme that oxidizes Dserine , an important co-agonist for the N-methyl-D-Aspartate receptor (NMDAR) [12]. "
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    ABSTRACT: Background: Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance. Methods: The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses. Results: The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results. Conclusions: Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.
    Full-text · Article · Feb 2016 · European Psychiatry
    • "In view of these similarities, the integration of categorical and dimensional approaches has been suggested of particular interest to the complete understanding of psychotic disorders (Peralta and Cuesta 2007). On the other hand, an important genetic overlap between SSD and BPD has been classically reported by both epidemiological (Gottesman 1991; Lichtenstein et al. 2006) and molecular studies (Owen et al. 2007). More recently, genome-wide approaches have evidenced a substantial shared polygenic contribution involving thousands of common genetic variants of small effect to the aetiology of these disorders (Lee et al. 2013). "
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    ABSTRACT: Objectives Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results The frequency of the haplotype C-C (rs645649–rs582262) was significantly increased in patients compared to controls (P = 0.0043), while the haplotype T-C-C-T-C-A (rs3763180–rs10484320–rs4960155–rs9379002–rs9405890–rs1475157) was more frequent in controls (P = 3.1 × 10−5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P = 0.005). Conclusions Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF.
    No preview · Article · Dec 2015 · The World Journal of Biological Psychiatry
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    • "Authors of the Diagnostic and Statistical Manual, 5th Edition (DSM-V) emphasise the importance of dimensional assessment of psychopathology (Heckers et al., 2013). The limitations of a categorical approach to diagnosis are well recognised: diagnostic groups have significant overlap in their clinical presentation, management strategies, prognosis, genetic underpinnings and clinical course (Kamphuis and Noordhof, 2009; Owen et al., 2007; Whitty et al., 2005; Bromet et al., 2011; Van et al., 2009). To date most FTD research has investigated only those diagnosed with schizophrenia, often drawing from hospital and institutional samples (Taylor et al., 1994; Berenbaum et al., 1985; Mortimer et al., 1990). "
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    ABSTRACT: Formal thought disorder (FTD) is a core feature of psychosis, however there are gaps in our knowledge about its prevalence and factor structure. We had two aims: first, to establish the factor structure of FTD; second, to explore the clinical utility of dimensions of FTD in order to further the understanding of its nosology. A cross-validation study was undertaken to establish the factor structure of FTD in first episode psychosis (FEP). The relative utility of FTD categories vs. dimensions across diagnostic categories was investigated. The prevalence of clinically significant FTD in this FEP sample was 21%, although 41% showed evidence of disorganised speech, 20% displayed verbosity and 24% displayed impoverished speech. A 3-factor model was identified as the best fit for FTD, with disorganisation, poverty and verbosity dimensions (GFI=0.99, RMR=0.07). These dimensions of FTD accurately distinguished affective from non-affective diagnostic categories. A categorical approach to FTD assessment was useful in identifying markers of clinical acuteness, as identified by short duration of untreated psychosis (OR=2.94, P<0.01) and inpatient treatment status (OR=3.98, P<0.01). FTD is moderately prevalent and multi-dimensional in FEP. Employing both a dimensional and categorical assessment of FTD gives valuable clinical information, however there may be a need to revise our conceptualisation of the nosology of FTD. The prognostic value of FTD, as well as its neural basis, requires elucidation. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Aug 2015 · Schizophrenia Research
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