Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
American Journal of Psychiatry (Impact Factor: 13.56). 07/1998; 155(6):829-31.
Source: PubMed

ABSTRACT The authors performed an analysis of their published chromosome 18 linkage data on 28 families in which there was bipolar disorder to test the potential of comorbid panic disorder to define a genetic subtype of bipolar disorder.
Families ascertained through probands with bipolar I disorder were stratified into three groups based on a history of panic disorder, panic attacks, or no panic attacks in the probands. Multipoint nonparametric linkage analysis was performed on data from bipolar I and II family members in each group.
Linkage scores for five consecutive 18q marker loci were highest in the families of the probands with panic disorder and lowest for the families of the probands without panic attacks.
This study supports the authors' previously reported clinical hypothesis of a genetic subtype of bipolar disorder identified by comorbid panic disorder. The hypothesis merits prospective testing.

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    • "In addition, the clinical heterogeneity of BP may be related to genetic heterogeneity. Studies hypothesize a relative genetic factor between BP and AD [31]. Since AD is the most prevalent comorbidity, past inconsistent genetic findings in BP may be related to the exclusion of AD comorbidity or not. "
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    ABSTRACT: Bipolar disorder (BP), especially bipolar II disorder (BP-II), is highly comorbid with anxiety disorder (AD). Monoaminergic dysfunction has been implicated in the pathogenesis of BP, it may be important to investigate genes such as the catechol-O-methyltransferase (COMT), involved in monoamine metabolism and brain-derived neurotrophic factor (BDNF) genes, modulating the monoamine system. We therefore examined the association of the COMT Val158Met and BDNF Val66Met polymorphisms with BP-II with and without comorbidity of AD, and possible interactions between these genes. Seven hundred and seventy-one participants were recruited: 314 with bipolar-II without AD, 117 with bipolar-II with AD, and 340 healthy controls. The genotypes of the COMT and BDNF polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant effect of the COMT and the BDNF polymorphisms, and a significant interaction effect for the Val/Val genotypes of the BDNF Val66Met polymorphism and the COMsT Val158Met Val/Met and Met/Met genotypes (P=0.007, 0.048) discriminated between BP-II without AD patients and controls. Our findings provide initial evidence that the COMT and BDNF genes interact in bipolar-II without AD. Our findings suggest the involvement of dopaminergic pathway in the pathogenesis of bipolar-II.
    Behavioural brain research 09/2012; 237C:243-248. DOI:10.1016/j.bbr.2012.09.039 · 3.39 Impact Factor
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    • "Many previous studies have reported that PD the most frequent comorbid AnxD in bipolar subjects (Chen & Dilsaver, 1995a; Kessler, 1999; McElroy et al., 2001). The link between BPD and PD has been demonstrated by genetic studies (Doughty, Wells, Joyce, Olds, & Walsh, 2004; MacKinnon et al., 1998). Even in the Epidemiological Catchment Area (ECA) study, lifetime prevalence of PD was 21.0% in those with BPD-I (Chen & Dilsaver, 1995a). "
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    ABSTRACT: High rates of anxiety disorders have been reported in bipolar disorders. The study aimed to investigate prevalence of anxiety disorders in remitted bipolar subjects and their influence on the illness severity. Bipolar subjects with anxiety disorders were younger, had earlier age at onset of illness, and were overrepresented by female subjects and those with earlier onset illness compared to those without anxiety disorder. The study demonstrated that (1) anxiety disorders are highly prevalent in bipolar subjects, (2) individual anxiety disorders, particularly SP and PD seem to have an effect on illness severity, (3) bipolar subjects with comorbid anxiety tend to have a poorer course and are less responsive to treatment, and (4) anxiety tends to be associated with an earlier age at onset of bipolar disorder (BPD) and results in a more complicated and severe disease course.
    Journal of anxiety disorders 02/2011; 25(5):661-7. DOI:10.1016/j.janxdis.2011.02.008 · 2.68 Impact Factor
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    • "Accordingly, molecular genetic linkage studies analyzing cosegregation of particular genetic markers with the disease of interest in pedigrees of affected families have yielded evidence for a variety of potential risk loci for anxiety disorders, e.g. for panic disorder on chromosomes 1p, 4q, 7p, 9q, 11p, 15q and 20p as well as on chromosomes 18, 13 and 22, respectively (Crowe et al., 1987; Fyer et al., 2006; Gelernter et al., 2001; Hamilton et al., 2003; Kaabi et al., 2006; Knowles et al., 1998; MacKinnon et al., 1998; Thorgeirsson et al., 2003), and for social or specific phobia on chromosomes 16q and 14p (Arnold et al., 2004; Gelernter et al., 2003, 2004; Smoller et al., 2008a; Stein et al., 1998). Also, molecular genetic association studies investigating the allelic frequency of a particular marker in an a-priori candidate gene in a patient sample as compared to a sample of healthy controls have reported a multitude of positive findings in panic disorder, particularly in genes coding for the cholezystokinin B (CCK- B) receptor (Hosing et al., 2004; Kennedy et al., 1999), the monoamine oxidase A (MAO-A) (Deckert et al., 1999), the catechol- O-methyltransferase (COMT) (Hamilton et al., 2002, Domschke et al., 2004; Rothe et al., 2006; Domschke et al., 2007), the serotonin receptor 1A (5-HT1A) (Huang et al., 2004; Rothe et al., 2004), the serotonin transporter (5-HTT) (Maron et al., 2004, 2005), the adenosine A2A receptor (Deckert et al., 1998; Hamilton et al., 2004), Rgs2 (Leygraf et al., 2006; Smoller et al., 2008c) and in the neuropeptide Y gene system (Domschke et al., 2008a). "
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    ABSTRACT: Anxiety disorders are frequent and burdensome psychiatric diseases. Despite their moderate to strong heritabilities, the search for candidate genes has been limited by methodological shortcomings hitherto, e.g., the use of clinically defined, but neurobiologically heterogeneous categorical phenotypes. Investigating neurobiological response patterns associated with fear processing as an intermediate phenotype might aid in overcoming these difficulties. The existing imaging literature on the neurobiological correlates of fear processing and anxiety disorders points to a pivotal role of the amygdala in the human fear circuit. Therefore, amygdala responsiveness to anxiety-related stimuli was suggested as an intermediate phenotype for anxiety disorders. The present article provides an overview of imaging genetic studies investigating genetic effects on amygdala responsiveness with particular emphasis on recent imaging genetic findings in anxiety-related traits, panic disorder and social phobia. The existing studies consistently reveal strong genetic effects on the responsiveness of the fear circuit, particularly of genetic variants previously discussed as potential susceptibility variants for anxiety, e.g., the COMT 158val allele or the 5-HTTLPR short allele. Further research will be necessary involving larger sample sizes to allow for investigating gene-gene and gene-environment interactions. More evolved statistical and neuroimaging methods such as effective connectivity measures could lead to a better understanding of imaging endophenotypes and the nature of gene-brain relationships. Longitudinal studies in patient samples will be required to elucidate how genetically influenced neurobiological intermediate phenotypes are associated with subtype, severity and the course of anxiety disorders, thereby having the potential for developing individualized therapy regimes derived from neurobiological research.
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