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: A recent genome-wide association study indicated that rs11098403, a single nucleotide polymorphism in the vicinity of NDST3, was strongly associated with the risk of schizophrenia in Caucasians. However, this relation has not been validated in other populations or ethnic groups. Herein, we conducted a case-control study to investigate the association of rs11098403 polymorphism with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. For the first time, we showed that the minor allele (G) of rs11098403 is closely associated with a reduced risk of schizophrenia (OR=0.614; 95% CI: 0.453-0.833; P=0.002; Power=0.832). Meanwhile, the G allele of rs11098403 seemed to reduce the schizophrenia risk via a dominant manner (GG+AG vs. AA, OR=0.526; 95% CI: 0.374-0.74; P<0.001). Furthermore, this association was further confirmed using an independent replication sample containing 267 schizophrenia patients and 400 control subjects with a Han Chinese descent (OR=0.652; 95% CI: 0.469-0.907; P=0.011; Power=0.772). Taken together, these findings demonstrate a significant association between rs11098403 and schizophrenia risk in Han Chinese, confirming the data that previously obtained from Caucasians.Neuroscience Letters 08/2014; · 2.06 Impact Factor
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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 01/2014; 5:277.
- Schizophrenia Research 09/2014; · 4.43 Impact Factor