The genetics of psychotic bipolar disorder

Johns Hopkins Hospital, 600 North Wolfe Street, Meyer 4-119, Baltimore, MD 21287, USA.
Current Psychiatry Reports (Impact Factor: 3.24). 05/2008; 10(2):178-89. DOI: 10.1007/s11920-008-0030-5
Source: PubMed


Psychotic features, defined as delusions or hallucinations, commonly occur in bipolar disorder (BP) and may be indicative of a more homogeneous form of the illness, with possible etiologic ties to schizophrenia. Several studies have shown that psychotic features aggregate in bipolar families, and increased interest in the molecular genetics of psychotic BP is emerging. Although preliminary, linkage studies of psychotic BP show replicated evidence for suggestive genome-wide linkage to chromosomes 8p and 13q, which have been implicated in prior linkage studies of schizophrenia and BP. Association studies of psychotic BP and subtypes such as mood-incongruent psychotic BP have uncovered modest positive results for several candidate schizophrenia susceptibility genes, including dysbindin, DAOA/G30, Disrupted-in-Schizophrenia-1, and neuregulin 1. These tentative results are consistent with the hypothesis that the subphenotype of psychotic BP may represent a clinical manifestation of "overlap" genes between schizophrenia and mood disorder syndromes.

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    • "In biological terms, over-activity of the mesolimbic dopamine pathway has been suggested as a contributor to the positive symptoms of psychosis including delusions and hallucinations; a number of genes in the dopamine pathway including COMT [20] and DTNBP1 [21] showed association with risk of psychosis. Other SCZ-associated genes were reported to be involved in psychotic susceptibility in different psychiatric disorders [22], [23], [24], [25], which included GABRB2 association with psychotic risk in BPD [26], suggesting that genetic modulation operates more on the psychosis endophenotype level rather than being localized to any particular psychiatric diagnosis. In keeping with this, a number of candidate susceptibility genes for psychiatric disorders were found to be involved in normal cognition-related behavior [27], [28], [29], [30], [31], suggesting that these genes could regulate both typical and impaired cognitive processes. "
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    ABSTRACT: The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition.
    PLoS ONE 04/2013; 8(4):e62322. DOI:10.1371/journal.pone.0062322 · 3.23 Impact Factor
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    • "A role for NRG1 in SZ has also been supported by animal studies using NRG1 and ErbB4 mutant mice (Gerlai et al., 2000; Stefansson et al., 2002; Bao et al., 2003; Corfas et al., 2004; Steinthorsdottir et al., 2004; Gu et al., 2005; Rimer et al., 2005), which exhibit behaviors similar to those of established rodent models of SZ (Lipska, 2004). NRG1 polymorphisms have been proposed as risk factors for several other common disorders, including Alzheimer's disease (Chaudhury et al., 2003; Go et al., 2005); epilepsy (early myoclonic encephalopathy; Backx et al., 2009), stroke (Shyu et al., 2004; Xu et al., 2004) breast cancer (Raj et al., 2001), multiple sclerosis (Cannella et al., 1999; Viehover et al., 2001), bipolar disorder (Thomson et al., 2007; Goes et al., 2008; Prata et al., 2009; Walker et al., 2010; Moon et al., 2011) and Hirschsprung Disease (Garcia-Barcelo et al., 2009; Tang et al., 2011). "
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    ABSTRACT: Background: Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. Methods: NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). Results: Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p≤0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. Conclusions: Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation.
    Schizophrenia Research 01/2013; 144(1-3). DOI:10.1016/j.schres.2012.12.017 · 3.92 Impact Factor
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    • "Currently, psychotic symptoms are considered as a criterion for severity of mood episodes in both Bipolar Disorder (BP) and Major Depressive Disorder (MDD) (A.P.A., 2000). No specification exists for defining a subgroup of lifetime Psychotic Mood Disorder (PMD) patients, though some studies suggest that these patients might share with schizophrenia not only symptom presentation, but also epidemiology (Murray et al., 2004), and, probably, genetic susceptibility (Craddock et al., 2006; Goes et al., 2008; Ivleva et al., 2010). Secondly, where some authors have argued that psychotic features have no validity in terms of prognosis, treatment or family history for mood disorders (Pope and Lipinski, 1978; Maj et al., 1990; Jager et al., 2005), others have found a poorer response to medications (Coryell et al., 1984), a worse short and long-term outcome (Coryell et al., 1982; Coryell et al., 1996; Coryell et al., 2001) and a more severe cognitive impairment (Grant et al., 2001; Hill et al., 2004; Jeste et al., 1996; Glahn et al., 2006). "
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    ABSTRACT: The nosological and clinical implications of psychotic features in the course of mood disorders have been widely debated. Currently, no specification exists for defining a subgroup of lifetime Psychotic Mood Disorder (PMD) patients. A total of 2178 patients were examined, including subjects with Bipolar Disorder (BP) type I (n=519) and II (n=207) and Major Depressive Disorder (n=1452). Patients were divided between PMD (n=645) and non-psychotic Mood Disorders (MD) (n=1533) by the lifetime presence of at least one mood episode with psychotic features. Subjects having a depressive episode at the time of assessment were also examined: HAM-D and YMRS scores were compared between MD and PMD subjects, both with and without current psychotic features. A diagnosis of BP-I, a higher familial load for BP, a higher number of mood episodes lifetime, and a higher prevalence of OCD and somatic comorbidities were all associated to PMD. A diagnosis of BP (OR=4.48) was the only significant predictor for psychosis. PMD with non-psychotic depression were apparently less severe than MD patients and had a lower rate of "non-responders" to AD treatment. Sub-threshold manic symptoms and suicidal risk were also more pronounced among PMD. The lack of information about number and polarity of previous psychotic mood episodes may be the major limitations of our study. BP diagnosis is the most significant predictor for psychosis in mood disorders. Non-psychotic mood episodes in PMD patients may be characterized by a distinctive symptom profile and, possibly, a different response to treatment.
    Journal of Affective Disorders 08/2011; 135(1-3):241-50. DOI:10.1016/j.jad.2011.07.027 · 3.38 Impact Factor
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