Etiology Of Bipolar Disorder Research Articles

The phospholipase C-gamma1 gene (PLCG1) and lithium-responsive bipolar disorder: re-examination of an intronic dinucleotide repeat polymorphism.

Twin, family and adoption studies have indicated that genetic susceptibility plays an important role in the etiology of bipolar disorder. Turecki et al. (1998) recently published preliminary evidence suggesting that bipolar patients with an excellent response to lithium treatment have a higher frequency of a specific dinucleotide repeat allele in the phospholipase Cgamma-1 (PLCG1) genomic region. The present work was undertaken to re-examine the finding by Turecki et al. in a sample of Norwegian lithium-treated bipolar patients sub-classified as lithium responders, non-responders, or partial responders/unclassified. The overall distribution of the PLCG1 dinucleotide repeat alleles was not significantly different between different categories of subjects. When analyzed according to presence or absence of different dinucleotide alleles, a PLCG1-8 repeat was more frequent among lithium responders vs controls. In line with Turecki et al., we also noticed a moderately over-representation of the PLCG1-5 repeat among the bipolar patients as compared to the controls.

Clock genes, feedback loops and their possible role in the etiology of bipolar disorders: an integrative model

Clock genes, which are found in all higher organisms including humans, play a central role in the generation and control of circadian rhythms. For example, the amount of protein encoded by the per gene in mice oscillates with a circadian frequency. The per gene is activated by a constitutively expressed heterodimeric protein encoded by thebmal1 and clock genes, and this activation is suppressed by the PER protein itself. The negative feedback of the PER protein on the expression of the per gene provides a framework for a basic circadian autoregulatory loop in mammals. These elements of biomolecular feedback loops are interpreted within a system theory as an elementary behavioral cycle consisting of intentional programs (the per gene), environmental objects (the BMAL1-CLOCK heterodimer) and the experiential realization of the intended programs (the level of PER protein). This single model enables the deduction of disturbances, which can be transferred to the criteria of bipolar disorders. It is hypothesized that mutations in clock genes lead to disturbances in molecular feedback loops, which on a behavioral level could appear as bipolar disorders. Finally, some implications for research and treatment of bipolar disorders are discussed.

Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study.

Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder. In France and Switzerland, 272 patients with bipolar disorder and 122 healthy subjects were typed for three polymorphic markers of the MAOA gene: the MAOA-CA repeat, the MAOA restriction fragment length polymorphism (RFLP), and a repeat directly adjacent to the variable number of tandem repeats (VNTR) locus. A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed between the female bipolar patients and comparison group. The results obtained in the French and Swiss population confirm findings from two studies conducted in the United Kingdom.

Association study of the tryptophan hydroxylase gene and bipolar affective disorder using family-based internal controls.

The tryptophan hydroxylase (TPH) gene encodes for the rate-limiting enzyme of the serotonin metabolism and, therefore, has to be considered a major candidate for association studies in affective disorders. Recently, an association between this gene and bipolar affective disorder has been reported in a French population. We sought to replicate this finding in a German sample. Allele frequencies of a biallelic polymorphism (A218C) of the TPH gene were determined in 95 bipolar I patients and their parents. Preferential transmission of alleles from heterozygous parents to bipolar offspring was tested with the "transmission disequilibrium test" (TDT), which eliminates the contribution of population stratification to an association finding. Our sample yielded a power >90% to detect the originally reported effect. Neither allele 218A nor allele 218C were preferentially transmitted from heterozygous parents to bipolar offspring. Our results, therefore, do not support the hypothesis that the TPH gene is involved in the etiology of bipolar disorder.

Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels.

The activity of inositol monophosphatase (IMPase), the lithium (Li)-inhibitable enzyme in the phosphatidylinositol (PI) signal transduction system, has recently been found significantly lower in lymphoblastoid cell lines from bipolar (BP) patients, particularly in Li-responders. To probe for possible quick detection of the disease and prediction of the therapeutic response we repeated our study in fresh lymphocytes. Since IMPase in fresh lymphocytes is inhibited in vivo by ongoing Li treatment and its pre-Li activity cannot be evaluated, IMPase mRNA levels were measured. Relative (to beta-actin) mRNA levels were quantified by reverse transcriptase (RT)-PCR in 5 drug-free and 31 drug-treated BP patients compared with 36 control subjects in fresh lymphocytes. In agreement with our findings with IMPase activity, the small group of drug-free BP patients exhibited approximately 2/3 reduction in IMPase relative mRNA levels compared to control subjects. Approximately 2-fold elevation of these levels toward control values was found for patients treated with Li and other mood stabilizers. The study further suggests the possible importance of IMPase in the aetiology of BP disorder and in the mediation of the therapeutic efficacy of Li. It may be that chronic inhibition of IMPase activity by Li results in up-regulation of its gene at the transcriptional level.

Disinhibition syndromes, secondary mania and bipolar disorder in old age

Background: The neurological literature concerning disinhibition syndromes and secondary mania has run in parallel to clinical reports of bipolar disorder in old age. Methods: A critical review was conducted of both the neurological and geriatric psychiatry literature in an attempt to integrate the two streams. Results: Disinhibition syndromes include lateralization to the right hemisphere and localization of lesions to the orbito-frontal and basotemporal cortex involving limbic and frontal connections (orbito-frontal circuit). Mania in old age is associated with late onset, heterogeneous neurological disorders and poor outcome. Conclusion: Bipolar disorders in old age may be understood in the context of affective vulnerability influenced by a specific neurobiologic substrate. Limitations: The clinical literature consists predominantly of small case series and anecdotal reports. Clinical relevance: Improved understanding of these syndromes may elucidate the pathogenesis and etiology of bipolar disorders and the neuropsychiatric syndromes affecting mood, motivation and behavioural disinhibition.

Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder.

This study aimed to evaluate aspects of second messenger function in the brain of suicide victims and patients with bipolar disorder. Inositol and its synthetic enzyme, inositol monophosphatase, were measured in postmortem brain samples of 10 suicide victims, eight patients with bipolar affective disorder, and 10 normal comparison subjects. The frontal cortex inositol levels of the suicide victims and the patients with bipolar disorder were significantly less than those of the normal comparison group. No differences in cerebellum or occipital cortex inositol levels were found among the three groups. The groups also showed no differences in inositol monophosphatase activity in any brain area. These results could suggest a deficiency of second messenger precursor in patients with bipolar disorder and suicide victims.

Lack of association between bipolar disorder and tyrosine hydroxylase: a meta-analysis.

Tyrosine hydroxylase (TH) is a candidate gene extensively explored in several association studies of bipolar disorder (BD). However, because of conflicting results of independent studies and low statistical power of individual studies to detect small differences between cases and controls, reliable conclusions are difficult to formulate. A method to obtain more reliable conclusions about the involvement of the TH locus in the etiology of BD is meta-analysis. We undertook a meta-analysis of studies that investigated the association between BD and TH genetic markers. The studies were identified by means of computerized searches of several databases, and the scanning of review articles and the reference lists of the primary articles identified. More than 60 publications were reviewed, and 9 relevant articles were included in this meta-analysis, with an overall sample of 1,069 subjects (547 cases and 522 normal controls). The overall odds ratio (and confidence interval) based on combining the results of the studies was 1.02 (0.68-1.54). Test of the null hypothesis that the mean log odds ratio equals zero (chi2 = 0.11; 5 df; P > 0.05) indicated that there was no overall association between bipolar disorder and tyrosine hydroxylase.

Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients.

We selected 83 patients with bipolar disorder type I or unipolar recurrent major depression and 71 healthy controls for genetic analysis of the tyrosine hydroxylase and the dopamine D4 receptor gene. No significant association was found between bipolar disorder type I and unipolar recurrent major depression and the polymorphisms located near these genes. Therefore, the hypothesis that the tyrosine hydroxylase and the dopamine D4 receptor genes may be involved in the etiology of bipolar disorder and unipolar recurrent major depression is not supported in our study.

A systematic evaluation of linkage studies in bipolar disorder.

Genetic factors have long been implicated in the aetiology of bipolar disorder (BD). During the past two decades several linkage studies have been carried out with the aim of identifying major genes. However, remarkable discrepancies in results both between and within studies have constituted a major problem. In order to elucidate some of these conflicts, we assessed the published literature on linkage studies of bipolar disorder, focusing on methodological issues. Studies published between January 1980 and December 1994 were identified by computerized literature searches and subsequent scanning of review articles, and the reference lists of the articles primarily identified. A set of defined inclusion and exclusion criteria was used to select studies for assessment. A total of 31 variables were determined, and pre-defined codes were assigned in a structured manner. More than 200 citations were reviewed, and 60 articles were included in this study. Descriptive statistical analyses of the variables, as well as associations between variables, are presented. The findings are discussed with regard to the possibility that, beyond the genetic complexity of the disorder itself, there are several other similarly complicated study design issues which should be more carefully observed. Moreover, the need for standardization of basic criteria to use and report clinical and analytical parameters employed in linkage studies is strongly suggested.

Association study of bipolar disorder using a functional polymorphism (Ser311→Cys) in the dopamine D2 receptor gene

Several pieces of evidence are consistent with the involvement of dopamine neurotransmission in the aetiology of bipolar disorder. We have tested the hypothesis that the functional mutation Ser311-->Cys of the dopamine D2 receptor gene confers susceptibility to bipolar disorder. There was no increased frequency of the mutation in 82 bipolar probands compared with 72 controls, showing that this mutation is not involved in the pathogenesis of (at least) the vast majority of cases of bipolar disorder. Our findings are consistent with other evidence from linkage and association studies against the involvement of the dopamine D2 receptor in bipolar disorder.

Bipolar disorder and the pseudoautosomal region: an association study.

From family, adoption, and twin studies it is clear that genetic factors play an important role in the etiology of bipolar disorder (McGuffin and Katz: The Biology of Depression, Gaskell, London, 1986). Recently Yoneda et al. (Am J Hum Genet 51:1172-1173, 1992) reported an association between an allele (A4) of a VNTR marker (DXYS20) for the pseudoautosomal region and bipolar disorder in a Japanese population. In order to test for this association in a Caucasian population, we have typed a sample of 52 subjects with bipolar disorder and 61 normal controls. The bipolar subjects are probands of multiple incidence families. The normal controls are an epidemiologically ascertained sample of middle-aged, unrelated individuals. The two groups were matched for sex and ethnic background. There were no significant differences in the allele or genotype frequencies of DXYS20 between the two groups. In particular, there was no significant difference in the frequency of the A4 allele in normal controls and bipolar patients (0.377 vs. 0.317, respectively). The prevalence of the A4 allele in bipolar patients and normal controls was 0.567 and 0.622, respectively. We were not able to replicate the results of the Yoneda et al. (1992) study.

Exclusion of close linkage of bipolar disorder to the dopamine D 3 receptor gene in nine Australian pedigrees

The recently cloned dopamine D 3 receptor (DRD3) gene is of potential relevance to the aetiology of bipolar disorder because of an almost exclusive expression in limbic tissue, the region of the brain putatively responsible for control of emotion. We therefore aimed to determine whether bipolar disorder in nine pedigrees (with 171 members) was linked to this receptor gene, which has been mapped to chromosomal region 3q 13.3. Linkage of bipolar disorder and recurrent depression to the DRD3 gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective illness (ranging from bipolar I alone to all affective disorders). Close linkage to the DRD3 gene was strongly excluded using each model and definition, and these conclusions persisted when a wide range of rates of ‘sporadic’ (non-genetic) presentations of illness were incorporated in the analysis.

Effect of hypophysectomy on urinary oestrogen in breast cancer.

<h3>Abstract</h3> Bipolar disorder (BD) is a severe mental disorder characterized by repeated mood swings. Although genetic factors are collectively associated with the etiology of BD, the underlying molecular mechanisms, particularly how environmental factors affect the brain, remain largely unknown. We performed promoter-wide DNA methylation analysis of neuronal and nonneuronal nuclei in the prefrontal cortex of patients with BD (N=34) and controls (N=35). We found decreased DNA methylation at promoters in both cell types in the BD patients compared to the controls. Gene Ontology (GO) analysis of differentially methylated region (DMR)-associated genes revealed enrichment of molecular motor-related genes in neurons, chemokines in both cell types, and ion channel- and transporter-related genes in nonneurons. Detailed analysis further revealed that growth cone- and dendrite-related genes, including <i>NTRK2</i> and <i>GRIN1</i>, were hypermethylated in neurons of BD patients. To assess the effect of medication, neuroblastoma cells were cultured under therapeutic concentrations of three different mood stabilizers (lithium, valproate, and carbamazepine). We observed that up to 37.9% of DMRs detected in BD overlapped with mood stabilizer-induced DMRs. Interestingly, mood stabilizer-induced DMRs showed the opposite direction of changes in DMRs in BD, suggesting the therapeutic effects of mood stabilizers on DNA methylation. Among the DMRs, 12 overlapped with loci identified by a previous genome-wide association study of BD. Finally, we performed qPCR analysis of 10 DNA methylation-related genes and found that <i>DNMT3B</i> was overexpressed in BD. The cell type-specific DMRs identified in this study will be useful for understanding the pathophysiology of BD.