Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder.
ABSTRACT Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian divide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects.
To investigate the possible role of NRG1 in bipolar disorder.
Genetic case-control association analysis.
Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services.
Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white).
We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls.
We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37; 95% confidence interval [CI], 1.03-1.80; P = .04). The effect size in our bipolar sample was similar to that in our schizophrenia sample (OR, 1.22; 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71; 95% CI, 1.29-2.59; P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64; 95% CI, 0.54-5.01).
Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features.
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ABSTRACT: With the advent of DSM 5 criticism has generally centered on a lack of biological validity of the diagnostic criteria. Part of the problem in describing a nosology of psychosis is the tacit assumption of multiple genetic causes each with an incremental loading on the clinical picture that fails to differentiate a clear underlying pathophysiology of high impact. The aim of this paper is to consolidate a primary theory of deficient muscarinic signaling underlying key clinical features of schizophrenia and its regulation by several important genetic associations including neuregulin, DISC and dysbindin. Secondary reductions in markers for GABAergic function and changes in the levels of interneuron calcium binding proteins parvalbumin and calbindin can be attributed to dysfunctional muscarinic transduction. A parallel association exists for cytokine production. The convergent pathway hypothesis is likewise used to model dopaminergic and glutamatergic theories of schizophrenia. The negative symptom dimension is correlated with dysfunction of Akt and ERK transduction, a major point of convergence. The present paradigm predicts the importance of a recent finding of a deletion in a copy number variant of PLCB1 and its potential use if replicated, as one of the first testable biological markers differentiating schizophrenia from bipolar disorder and further subtyping of schizophrenia into deficit and non-deficit. Potential limitations of PLCB1 as a prospective marker are also discussed.Frontiers in Pharmacology 12/2014; 5:277. DOI:10.3389/fphar.2014.00277
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ABSTRACT: White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In this review, we evaluate published diffusion tensor imaging (DTI) studies comparing first degree relatives of SZ and BD patients and healthy control subjects. We searched PubMed, Embase and PsychInfo for DTI studies which included an unaffected relative and a healthy comparison group. 22 studies fulfilled the inclusion criteria. WM abnormalities were found in many diverse regions in relatives of SZ patients. Although the findings were not completely consistent across studies, the most implicated areas were the frontal and temporal WM regions and the corpus callosum. Studies in relatives of BD patients were fewer in number with less consistent findings reported across studies. Our review supports the concept of WM abnormalities as an endophenotype in SZ, with somewhat weaker evidence in BD, but larger and higher quality studies are needed to make a definitive comment. Copyright © 2014 Elsevier B.V. All rights reserved.Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.12.008 · 4.43 Impact Factor