Mitochondrial dysfunction in bipolar disorder

Mitochondrial dysfunction is implicated in bipolar disorder based on the following lines of evidence: 1) Abnormal brain energy metabolism measured by 31 P‐magnetic resonance spectroscopy, that is, decreased intracellular pH, decreased phosphocreatine (PCr), and enhanced response of PCr to photic stimulation. 2) Possible role of maternal inheritance in the transmission of bipolar disorder. 3) Increased levels of the 4977‐bp deletion in mitochondrial DNA (mtDNA) in autopsied brains. 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation. Based on these findings, we searched for mtDNA mutations/polymorphisms associated with bipolar disorder and found that 5178C and 10398A polymorphisms in mtDNA were risk factors for bipolar disorder. The 5178C genotype was associated with lower brain intracellular pH. mtDNA variations may play a part in the pathophysiology of bipolar disorder through alteration of intracellular calcium signaling systems. The mitochondrial dysfunction hypothesis, which comprehensively accounts for the pathophysiology of bipolar disorder, is proposed.     

Mitochondrial DNA sequence diversity in bipolar affective disorder

OBJECTIVE: Point mutations in mitochondrial DNA (mtDNA) are one mechanism that could explain the apparent excess maternal transmission of bipolar affective disorder observed in some families. The authors sequenced the mtDNA from probands with bipolar disorder and tested nucleotide variants for association with the disorder. METHOD: The entire 16.5 kilobase mitochondrial genome was sequenced in nine unrelated probands selected from large pedigrees with exclusively maternal transmission of bipolar affective disorder. Compared to a reference sequence, variants were detected at 107 nucleotide positions. Fifteen variants of possible pathogenic significance were selected for further study. These variants were assayed in 93 unrelated probands with bipolar I, bipolar II, or schizoaffective-manic disorder and 63 comparison subjects, all of whom were classified into the major groups comprising the European mtDNA haplotype structure (haplogroups).RESULTS: The major European haplogroups were represented at the expected frequencies among both probands and comparison subjects. There was no significant difference between probands and comparison subjects in the frequency of any variant, although odds ratios >2 or <0.5 were observed for four variants. Frequencies of these four variants were similar in probands and haplogroup-matched comparison subjects. The results of all comparisons were essentially unchanged when probands from families with an apparently paternal transmission pattern were excluded.CONCLUSIONS: The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.     

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.     

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton ((1)H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus ((31)P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.     

Recent progress in the search for genes for bipolar disorder

Over many decades, much evidence has been accumulated to demonstrate the strong role of genetic factors in bipolar disorder. Recently, genetic studies of bipolar disorder have turned from proving the role of genetics to identifying the specific genes involved. This has been made possible by the development of powerful methods to identify disease genes by their locations on chromosomes, an approach termed postitional cloning. Currently, about a dozen regions in the genome have been implicated as the location of susceptibility genes for bipolar disorder. Several of these have been replicated and will likely lead to the identification of novel disease mechanisms. An intriguing development is that a few of these are the same locations implicated in studies of schizophrenia, suggesting a greater genetic relationship between these disorders than had been previously thought. It is hoped that the identification of novel disease genes will lead to a better understanding of the pathophysiology of bipolar disorder and to the development of more effective treatments.     

Update on the search for genes for bipolar disorder

The past several years have witnessed a series of exciting advances in the genetics of bipolar disorder. Much of this progress has been catalyzed by data and tools emerging from the Human Genome Project. Whereas 4 years ago several chromosomal regions had been identified in linkage studies, now several of the genes in these regions may have been identified. A genetic overlap between bipolar disorder and schizophrenia that was hinted at, now seems certain. Our picture of the genetics of bipolar disorder is also different, with more rather than fewer genes being likely. As daunting as the problem seems to have become, powerful tools have been developed that promise even greater advances. This update reviews this recent progress, and speculates on the future.     

The COMT and DRD3 genes interacted in bipolar I but not bipolar II disorder

Abstract

Objectives. Clarifying the association between bipolar I and bipolar II disorders at the genetic level is essential for improving our understanding of them. In this study, we evaluated the hypothesis that the dopaminergic polymorphisms are risk factors for bipolar disorders. We examined the association between the catechol-O-methyltransferase (COMT) Val158Met and dopamine D3 receptor (DRD3) Ser9Gly polymorphisms and bipolar I and II disorders, as well as possible interactions between these genes. Methods. Seven hundred and eleven participants were recruited: 205 with bipolar I, 270 with bipolar II, and 236 healthy controls. The genotypes of the COMT Val158Met and DRD3 Ser9Gly polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. Results. Logistic regression analyses showed a statistically significant main effect for the Met/Met genotype of the COMT Val158Met polymorphism (P=0.032) and a significant interaction effect for the Met/Met genotype of the COMT Val158Met and Ser/Ser genotypes of the DRD3 Ser9Gly polymorphism (P=0.001) predicted bipolar I patients. However, there was no association between the COMT Val158Met or DRD3 Ser9Gly and bipolar II. Conclusions. We provide initial evidence that the COMT Val158Met and DRD3 Ser9Gly genotypes interact in bipolar I and bipolar II disorders and that bipolar I and bipolar II are genetically distinct.     

Assessing oxidative pathway genes as risk factors for bipolar disorder

Fullerton JM, Tiwari Y, Agahi G, Heath A, Berk M, Mitchell PB, Schofield PR. Assessing oxidative pathway genes as risk factors for bipolar disorder.
Bipolar Disord 2010: 12: 550–556. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. Methods: Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). Results: Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global χ² = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, χ² = 9.526, p = 0.002, corrected p = 0.029). Conclusions: Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder.     

Genetic association of cyclic AMP signaling genes with bipolar disorder

The genetic basis for bipolar disorder (BPD) is complex with the involvement of multiple genes. As it is well established that cyclic adenosine monophosphate (cAMP) signaling regulates behavior, we tested variants in 29 genes that encode components of this signaling pathway for associations with BPD type I (BPD I) and BPD type II (BPD II). A total of 1172 individuals with BPD I, 516 individuals with BPD II and 1728 controls were analyzed. Single SNP (single-nucleotide polymorphism), haplotype and SNP × SNP interactions were examined for association with BPD. Several statistically significant single-SNP associations were observed between BPD I and variants in the PDE10A gene and between BPD II and variants in the DISC1 and GNAS genes. Haplotype analysis supported the conclusion that variation in these genes is associated with BPD. We followed-up PDE10A''s association with BPD I by sequencing a 23-kb region in 30 subjects homozygous for seven minor allele risk SNPs and discovered eight additional rare variants (minor allele frequency <1%). These single-nucleotide variants were genotyped in 999 BPD cases and 801 controls. We obtained a significant association for these variants in the combined sample using multiple methods for rare variant analysis. After using newly developed methods to account for potential bias from sequencing BPD cases only, the results remained significant. In addition, SNP × SNP interaction studies suggested that variants in several cAMP signaling pathway genes interact to increase the risk of BPD. This report is among the first to use multiple rare variant analysis methods following common tagSNPs associations with BPD.     

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.     

Rapid cycle bipolar disorder: the present situation]

In 1974, rapid cycling bipolar disorder has been defined by Dunner and Fieve as four or more episodes of depression or mania per year. Twenty year later, this definition appeared for the first line in an international classification of mental disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. The rapid cycling phenomenon has been since studied with new adapted modified criteria taking into account different duration of affective episodes which characterise rapid cycling. Rapid cycling is associated with a low prophylactic efficacy of lithium and often represents a difficult approach for the clinician. Clinical aspects, influence of antidepressants associated with acceleration of cycles and possible therapeutic trials including non pharmaceutical treatment are discussed.     

Melatonin, circadian rhythms, and the clock genes in bipolar disorder

Sleep disturbances and dysregulation of circadian rhythms are core elements of bipolar disorder that might be involved in its pathogenesis. It has been proposed that patients with bipolar disorder have an abnormally shifted or arrhythmic circadian system and that the disturbance of circadian rhythms may be caused by an alteration in the circadian clock machinery. Chronotherapeutic strategies based on controlled exposures to environmental stimuli that act on biological rhythms have shown good efficacy in the treatment of illness episodes, thus confirming ex juvantibus the clinical relevance of internal timing in this illness.     

双相障碍与睡眠障碍共同致病基因的研究进展

双相障碍是一种严重的精神障碍,常有昼夜节律紊乱、失眠、睡眠过多等症状,其发生发展受到遗传因素的影响。睡眠障碍有昼夜节律紊乱、失眠等症状,同样和遗传相关。由于双相障碍与睡眠障碍的遗传机制有重叠之处,本文对双相障碍与睡眠障碍的共同致病基因进行综述,回顾两种疾病的基因关联性研究,总结可能的共同致病基因,为疾病的发生发展以及预防和治疗提供新思路。     

Association analysis between dopamine receptor genes and bipolar affective disorder.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.