Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.     

An overview of the genetics of psychotic mood disorders

This article presents a conceptual review of the genetic underpinnings of psychotic mood disorders. Both unipolar and bipolar forms of mood disorder sometimes feature psychotic symptoms. Some evidence from epidemiological research suggests that psychotic forms of mood disorder specifically might be heritable. Linkage studies of mood disorders in general have also provided some support for that notion, as have associated studies involving serotonin and dopamine genes and psychotic mood disorder. Some research suggests there might be a genetic connection between schizophrenia and bipolar disorder, undermining the Kraepelinian dichotomous classification of the psychoses. Future research should continue to examine psychotic forms of mood disorder using both epidemiological and molecular approaches.     

Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? evidence fromDISC1, GRIK4 andNRG1

Depression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders, GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders.     

The familial aggregation of psychotic symptoms in bipolar disorder pedigrees

OBJECTIVE: Symptomatic overlap between affective disorders and schizophrenia has long been noted. More recently, family and linkage studies have provided some evidence for overlapping genetic susceptibility between bipolar disorder and schizophrenia. If shared genes are responsible for the psychotic manifestations of both disorders, these genes may result in clustering of psychotic symptoms in some bipolar disorder pedigrees. The authors tested this hypothesis in families ascertained for a genetic study of bipolar disorder. METHOD: Rates of psychotic symptoms-defined as hallucinations or delusions-during affective episodes were compared in families of 47 psychotic and 18 nonpsychotic probands with bipolar I disorder. The analysis included 202 first-degree relatives with major affective disorder. RESULTS: Significantly more families of psychotic probands than families of nonpsychotic probands (64% versus 28%) contained at least one relative who had affective disorder with psychotic symptoms. Significantly more affectively ill relatives of psychotic probands than of nonpsychotic probands (34% versus 11%) had psychotic symptoms. An analysis of clustering of psychotic subjects across all families revealed significant familial aggregation. Clustering of psychosis was also apparent when only bipolar I disorder was considered the affected phenotype. CONCLUSIONS: Psychotic bipolar disorder may delineate a subtype of value for genetic and biological investigations. Families with this subtype should be used to search for linkage in chromosomal regions 10p12-13, 13q32, 18p11.2, and 22q11-13, where susceptibility genes common to bipolar disorder and schizophrenia may reside. Putative schizophrenia-associated biological markers, such as abnormal evoked response, oculomotor, and neuroimaging measures, could similarly be explored in such families.     

Schizophrenia and bipolar disorder are distinguished mainly by differences in neurodevelopment

This paper examines the commonalities and the differences between schizophrenia and bipolar disorder. Recent studies suggest a possible overlap in genetic susceptibility to the two conditions. However, while the influence of early environmental effects, particularly obstetric complications, has been established for schizophrenia, no such replicable association with bipolar disorder has been found. Structural abnormalities of the brain have been identified in both schizophrenia and bipolar disorder, but while the volume of the amygdala and hippocampus appears decreased in schizophrenia, this is not the case in bipolar disorder; indeed there are some suggestions of increased volume of the amygdala. Furthermore, schizophrenia is characterised by lower IQ, executive function and verbal memory, but there is little evidence of trait neuropsychological deficits in bipolar disorder. Similarly, premanic children do not show the cognitive and neuromotor impairments characteristic of those destined to develop schizophrenia. The most plausible explanation is that the two conditions share some genetic predisposition but differ in that schizophrenia but not bipolar disorder is subject to additional genes or early environmental hazards causing neurodevelopmental impairment.     

Association of the dysbindin gene with bipolar affective disorder

OBJECTIVE: In the study of bipolar affective disorder and schizophrenia, there is some evidence suggesting a phenotypic and genetic overlap between the two disorders. A possible link between bipolar affective disorder and schizophrenia remains arguable, however. The authors hypothesized that dysbindin, which is a probable susceptibility gene for schizophrenia, was associated with bipolar affective disorder and tested this hypothesis using a case-control design study. METHOD: Participants included 213 patients with bipolar I disorder and 197 comparison subjects. In each subject, 10 polymorphisms in the dysbindin gene were genotyped and assessed. RESULTS: Two polymorphisms showed individual genotypic association with bipolar I disorder. Multiple marker haplotypes were more strongly associated, with the rarer of the two common haplotypes being overrepresented in the patients with bipolar affective disorder. A similar finding was reported in patients with schizophrenia in a previous study. CONCLUSIONS: Findings suggest that the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder, which underscores a potentially important area of etiological overlap with schizophrenia. The existence of shared genetic risk factors will, in time, lead to changes in the current nosology of major psychoses.     

Genetic models of schizophrenia and bipolar disorder

Abstract Schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies.     

Genetic Relationships Between Schizophrenia,Bipolar Disorder,and Schizoaffective Disorder

There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant.Key words: family studies, twin, adoption, GWAS, copy number variants     

The boundaries of schizophrenia: Overlap with bipolar disorders

The extent to which schizophrenia and bipolar disorder converge or diverge across a range of domains is a fundamental construct in psychiatric nosology and neuroscience. Both conditions share overlapping symptomatology and the Kraepelinian dichotomy that course of illness helps define and separate each condition longitudinally is, at best, contentious. Schizophrenia and bipolar disorders both show high rates of heritability, with recent whole genome linkage studies providing some evidence for shared genetic liability. On the other hand, the available evidence suggests a greater influence of nongenetic factors in schizophrenia than in bipolar disorders. There are also subtle differences in structural brain abnormalities and in cellular architecture between these conditions. In the area where perhaps heretofore there was the greatest divergence, emerging information suggests an overlap in therapeutic efficacy between medications used for the treatment of schizophrenia and those agents used for treating mood disorders. Pertinent aspects of etiopathogenesis as well as recent publications that address overlapping domains between schizophrenia and mood disorders are reviewed.     

Hypothesis: grandiosity and guilt cause paranoia; paranoid schizophrenia is a psychotic mood disorder; a review

Delusional paranoia has been associated with severe mental illness for over a century. Kraepelin introduced a disorder called "paranoid depression," but "paranoid" became linked to schizophrenia, not to mood disorders. Paranoid remains the most common subtype of schizophrenia, but some of these cases, as Kraepelin initially implied, may be unrecognized psychotic mood disorders, so the relationship of paranoid schizophrenia to psychotic bipolar disorder warrants reevaluation. To address whether paranoia associates more with schizophrenia or mood disorders, a selected literature is reviewed and 11 cases are summarized. Comparative clinical and recent molecular genetic data find phenotypic and genotypic commonalities between patients diagnosed with schizophrenia and psychotic bipolar disorder lending support to the idea that paranoid schizophrenia could be the same disorder as psychotic bipolar disorder. A selected clinical literature finds no symptom, course, or characteristic traditionally considered diagnostic of schizophrenia that cannot be accounted for by psychotic bipolar disorder patients. For example, it is hypothesized here that 2 common mood-based symptoms, grandiosity and guilt, may underlie functional paranoia. Mania explains paranoia when there are grandiose delusions that one's possessions are so valuable that others will kill for them. Similarly, depression explains paranoia when delusional guilt convinces patients that they deserve punishment. In both cases, fear becomes the overwhelming emotion but patient and physician focus on the paranoia rather than on underlying mood symptoms can cause misdiagnoses. This study uses a clinical, case-based, hypothesis generation approach that warrants follow-up with a larger representative sample of psychotic patients followed prospectively to determine the degree to which the clinical course observed herein is typical of all such patients. Differential diagnoses, nomenclature, and treatment implications are discussed because bipolar patients misdiagnosed with schizophrenia are severely misserved.     

Boosting the Power of Schizophrenia Genetics by Leveraging New Statistical Tools

Genome-wide association studies (GWAS) have identified a large number of gene variants associated with schizophrenia, but these variants explain only a small portion of the heritability. It is becoming increasingly clear that schizophrenia is influenced by many genes, most of which have effects too small to be identified using traditional GWAS statistical methods. By applying recently developed Empirical Bayes statistical approaches, we have demonstrated that functional genic elements show differential contribution to phenotypic variance, with some elements (regulatory regions and exons) showing strong enrichment for association with schizophrenia. Applying related methods, we also showed abundant genetic overlap (pleiotropy) between schizophrenia and other phenotypes, including bipolar disorder, cardiovascular disease risk factors, and multiple sclerosis. We estimated the number of gene variants with effects in schizophrenia and bipolar disorder to be approximately 1.2%. By applying our novel statistical framework, we dramatically improved gene discovery and detected a large number of new gene loci associated with schizophrenia that have not yet been identified with standard GWAS methods. Utilizing independent schizophrenia substudies, we showed that these new loci have high replication rates in de novo samples, indicating that they likely represent true schizophrenia risk genes. The new statistical tools provide a powerful approach for uncovering more of the missing heritability of schizophrenia and other complex disorders. In conclusion, the highly polygenic architecture of schizophrenia strongly suggests the utility of research approaches that recognize schizophrenia neuropathology as a complex dynamic system, with many small gene effects integrated in functional networks.Key words: GWAS, polygenicity, pleiotropy, empirical Bayes approach, molecular genetics     

Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: Evidence,limitations, and implications

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting and modifying growth, development, and survival of neuronal populations, and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. Based on several lines of evidence, BDNF has been hypothesized to play an important role in the pathogenesis of mood disorder and the therapeutic action of at least some effective treatments. The gene encoding BDNF lies on the short arm of chromosome 11 in a region where some linkage studies of bipolar disorder have reported evidence for a susceptibility gene. BDNF can, thus, be considered as an attractive candidate gene for involvement in the pathogenesis of bipolar disorder, and two recent family-based association studies have provided evidence that one or more sequence variants within or near the BDNF gene show an association with disease susceptibility. These findings are of great interest and may open up a new chapter in the understanding of the causation and treatment of bipolar disorder. However, it is still early in the genetic investigation of BDNF in bipolar disorder, and it is important that these findings are replicated in large independent samples and that functional studies can confirm and characterize the pathogenic relevance of this genetic variation.     

Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.     

Malic enzyme 2 and susceptibility to psychosis and mania

Previous studies have identified a putative gene locus for both schizophrenia and bipolar disorder in the chromosome 18q21 region. To identify candidate genes associated with these disorders we completed fine mapping analyses (using microsatellite markers) in 152 families from the Central Valley of Costa Rica (CVCR) (376 total subjects, 151 with a history of psychosis, 97 with a history of mania). Microsatellite analyses showed evidence of association at two contiguous markers, both located at the same genetic distance and spanning approximately 11 known genes. In a corollary gene expression study, one of these genes, malic enzyme 2 (ME2), showed levels of gene expression 5.6-fold lower in anterior cingulate tissue from post-mortem bipolar brains. Subsequent analysis of individual SNPs in strong linkage disequilibrium with the ME2 gene revealed one SNP and one haplotype associated with the phenotype of psychosis in the CVCR sample. ME2 interacts directly with the malate shuttle system, which has been shown to be altered in schizophrenia and bipolar disorder, and has roles in neuronal synthesis of glutamate and gamma-amino butyric acid. The present study suggests that genetic variation in or near the ME2 gene is associated with both psychotic and manic disorders, including schizophrenia and bipolar disorder.     

A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association

Norepinephrine is one of the neurotransmitters which has been implicated in the pathogenesis of mood disorders and schizophrenia. The norepinephrine transporter (NET) gene may be a candidate gene for the study of the genetics of these disorders. In this study, 198 patients with schizophrenia and 100 patients with bipolar disorder were analysed for a silent mutation 1287 A/G, located in the coding region (exon 9) of the NET gene, to determine the association between this polymorphism of the NET gene and bipolar disorder or schizophrenia. No association was found between the studied polymorphism of the NET gene and either bipolar disorder or schizophrenia.     

Matrix Metalloproteinase-9 Gene and Bipolar Mood Disorder

Matrix metalloproteinase-9 (MMP-9) plays a role in many pathological conditions (e.g., cancer and heart disease). Recently, MMP-9 has been implicated in various aspects of brain functions (e.g., neuroplasticity and epileptogenesis) and thus, we hypothesized that MMP-9 gene may be associated with bipolar mood disorder. The study was performed on 416 patients with bipolar mood disorder, including 75 patients with bipolar II type of the illness, and in 558 healthy control persons. A functional −1562C/T polymorphism of the MMP-9 gene was genotyped in all subjects. Patients with bipolar mood disorder had significant preponderance of T allele versus C allele of 1562C/T polymorphism of the MMP-9 gene, compared to healthy control subjects. The higher frequency of T allele compared to healthy subjects was especially evident in a subgroup of patients with bipolar disorder, type II. The results may provide the first evidence for an involvement of the MMP-9 gene in the pathogenesis of bipolar mood disorder. They may also contribute to explaining genetic connection between bipolar mood disorder and some somatic illnesses. In the light of our results obtained with this polymorphism in schizophrenia, we speculate that the MMP-9 gene may be a common susceptibility gene to major psychoses with different allelic variants occurring in bipolar illness and schizophrenia.     

Genetics in schizophrenia: where are we and what next?

Understanding the genetic basis of schizophrenia continues to be major challenge. The research done during the last two decades has provided several candidate genes which unfortunately have not been consistently replicated across or within a population. The recent genome-wide association studies (GWAS) and copy number variation (CNV) studies have provided important evidence suggesting a role of both common and rare large CNVs in schizophrenia genesis. The burden of rare copy number variations appears to be increased in schizophrenia patients. A consistent observation among the GWAS studies is the association with schizophrenia of genetic markers in the major histocompatibility complex (6p22.1)-containing genes including NOTCH4 and histone protein loci. Molecular genetic studies are also demonstrating that there is more overlap between the susceptibility genes for schizophrenia and bipolar disorder than previously suspected. In this review we summarize the major findings of the past decade and suggest areas of future research.     

Cognitive impairment and functional outcome in schizophrenia and bipolar disorder

Cognitive impairment in schizophrenia and that in bipolar disorder share some similarities. However, more literature exists on cognitive impairment in schizophrenia than in bipolar disorder. The NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Initiative has identified several cognitive domains that are dysfunctional in schizophrenia and should be considered in the context of clinical trials. Cognitive impairments in these domains are also seen in bipolar disorder, but they tend to be milder. These impairments seem to be a core feature of schizophrenia and exist outside of mood episodes in bipolar disorder. Impairments are present in unaffected relatives of patients with schizophrenia or bipolar disorder, can serve as an endophenotype for both illnesses, and are linked to community functioning.     

Genetics of schizophrenia and affective disorders

The molecular-genetic basis of non-mendelian, genetically influenced disorders (complex disorders) is beginning to be uncovered. Recently, major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder was achieved. We provide a comprehensive overview of recent results of linkage and association studies in schizophrenia and bipolar disorder. Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited. Multiple limitations of current research strategies in the search of disposition genes of complex disorders have to be considered; alternative phenotype definitions, genome-wide association studies and parallel investigation of epigenetic misregulations might overcome these limitations.     

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.