Interactions In Schizophrenia Research Articles

Immune system and glucose metabolism interaction in schizophrenia: A chicken–egg dilemma

Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-β) appear to be state markers, whereas IL-12, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia.

Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model

Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug-drug interactions. However, the pharmacological and behavioral mechanisms underlying drug-drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug-drug conditioning (DDC) between haloperidol (a typical antipsychotic) or olanzapine (atypical antipsychotic) and citalopram (a selective serotonin reuptake inhibitor). A rat two-way conditioned avoidance response paradigm was used to measure antipsychotic activity and determine how DDC may alter the antipsychotic efficacy in this model. Following acquisition of the avoidance response, rats were then randomly assigned to receive vehicle, citalopram (10.0 mg/kg, intraperitoneally), haloperidol (0.05 mg/kg, subcutaneously), olanzapine (1.0 mg/kg, subcutaneously), combined haloperidol with citalopram, or combined olanzapine with citalopram treatment for seven avoidance test sessions. In comparison with antipsychotic treatment alone, combined treatment with citalopram potentiated the antiavoidance effect of olanzapine or haloperidol (to a lesser extent) during the seven drug-test sessions. In addition, repeated pairing of citalopram with haloperidol or olanzapine caused citalopram to show a newly acquired avoidance-disruptive effect. This effect was context specific because citalopram paired with haloperidol or olanzapine outside the avoidance testing context (i.e. home cages) did not show such an effect. These findings indicate that concurrent antidepressant and antipsychotic treatments may engender a DDC process that follows the general Pavlovian associative conditioning principles. They also indicate that adjunctive citalopram treatment may enhance the antipsychotic efficacy of haloperidol and olanzapine in the treatment of schizophrenia.

Cognition-emotion interactions are modulated by working memory capacity in individuals with schizophrenia

Prior research provides evidence for aberrant cognition-emotion interactions in schizophrenia. In the current study, we aimed to extend these findings by administering the “distractor devaluation” task to 40 individuals with schizophrenia and 32 demographically matched healthy controls. The task consisted of a simple visual search task for neutral faces, followed by an evaluative response made for one of the search items (or a novel item) to determine whether prior attentional selection results in a devaluation of a previously unattended stimulus. We also manipulated working memory demands by preceding the search array with a memory array that required subjects to hold 0, 1, or 2 items in working memory while performing the search array and devaluation task, to determine whether the normative process by which attentional states influence evaluative response is limited by working memory capacity. Results indicated that individuals with schizophrenia demonstrated the typical distractor devaluation effect at working memory load 0, suggesting intact evaluative response. However, the devaluation effect was absent at working memory loads of 1 and 2, suggesting that normal evaluative responses can be abolished in people with schizophrenia when working memory capacity is exceeded. Thus, findings provide further evidence for normal evaluative response in schizophrenia, but clarify that these normal experiences may not hold when working memory demands are too high.

Poster #107 GENETIC AND FUNCTIONAL ANALYSIS OF EGR FAMILY GENES IN SCHIZOPHRENIA

Early growth response (EGR) genes are thought to have a role in the pathogenesis of schizophrenia because of their conserved DNA binding domain and biologically activity in neuronal plasticity. This zinc-finger motif could influence gene post-translational modification and expression. The multigenetic association model, using markers in genes of similar or antagonistic biological effects within a signal pathway or gene family, might be more appropriate to this aspect of the schizophrenia hypothesis than the single gene strategy. In this study we investigated the role of EGR1, EGR2, EGR3 and EGR4 within the EGR family. Taqman technology was used to examine 12 single nucleotide polymorphisms (SNPs) covering these four genes in 2044 Chinese Han subjects. Case–control analyses were performed to detect association of these 4 genes with schizophrenia and multifactor dimensionality reduction (MDR) analysis was employed to examine their potential gene–gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1–4 and the risk of schizophrenia nor was any such association found with regard to interaction within EGR1–4 (pmin = 0.623, CV Consistency = 10/10). We concluded that although multiple candidate genes are involved in schizophrenogenic development, the EGR family may not play a major role in schizophrenia susceptibility in the Chinese Han population.

Movement-related potentials point towards an impaired tuning of reafferent sensory feedback by preceding motor activation in schizophrenia

The link between focal motor system activation and reafferent sensory feedback is thought to be crucial for the perception that a movement is actively performed. In this article, we examine how schizophrenia affects the relationship between motor and somatosensory system activation. Movement-related potential source analysis allowed us to separate and compare motor activation deficits and reafferent feedback processing. We analyzed lateralized movement-related potentials during choice reaction movements in 16 subjects with schizophrenia/schizoaffective disorder. These subjects had partial remissions with predominantly negative symptoms and were compared to an age-matched healthy control group. In the schizophrenia/schizoaffective group, dipole source analysis indicated a significantly reduced lateralized sensorimotor activation immediately preceding movement execution. In contrast, activation by reafferent feedback was relatively unimpaired. Subjects with schizophrenia/schizoaffective disorder lacked a focal motor and reafferent sensory processing correlation, which can be identified through a significantly different regression slope from healthy controls. Reduced action-related motor system activation in subjects with schizophrenia/schizoaffective disorder was associated with preserved activation by reafferent sensory feedback. Most importantly, motor-sensory tuning, i.e. a specific enhancement of sensory information necessary to monitor movements, could not be found in subjects with schizophrenia/schizoaffective disorder. Our data provide further evidence for disturbed motor-sensory interactions in schizophrenia.

The Impact of Impaired “Theory of Mind” on Social Interactions in Schizophrenia

Given the importance of social dysfunction in schizophrenia, many studies have explored how social cognition, and, particularly, Theory of Mind (ToM) may affect patients' social interactions. In the present study, we investigated the impact of ToM deficits on social interactions, taking into account overall neuropsychological functioning as well as clinical and demographic characteristics. We assessed 28 patients with schizophrenia and 30 healthy participants on a series of tasks including tests of ToM, neuropsychological tests focused on functions potentially relevant to ToM and role plays as an indicator of social interactions. Patients performed more poorly than healthy controls across most ToM and some of the neuropsychological tests. Correlations and hierarchical regression analyses indicated the impact of some, but not all, facets of ToM on patients' social interactions, over and above neuropsychological functioning, positive and negative symptom ratings, duration of illness and demographic characteristics. These findings suggest that remediation of ToM deficits in patients with schizophrenia may help to improve their social interactions.

Interaction between COMT haplotypes and cannabis in schizophrenia: A case-only study in two samples from Spain

Cannabis use is one of the environmental factors with more solid evidence contributing to schizophrenia risk, especially in genetically susceptible individuals. One of the genes that may interact with cannabis is COMT, although available data are scarce. Here, we present a case-only study of the putative COMT–cannabis interaction in schizophrenia. Two Spanish samples from Santiago de Compostela and Valencia were screened for cannabis use. One hundred and fifty five individuals from a total of 748 patients were identified as cannabis users. Five SNPs in COMT, defining three common functional haplotypes with different enzymatic activities, were genotyped and analyzed for association at the SNP, haplotype and genotype levels. An association was detected between cannabis use and low activity variants (P<0.01) in the joint analysis and results were consistent between the two samples. Schizophrenic subjects homozygous for the Met allele at rs4680 doubled the probability of lifetime prevalence of cannabis use in comparison to Val homozygous (Mantel–Haenszel OR=2.07, 95% CI: 1.27–3.26, P=0.0031, in the combined sample). These data are in contrast to those from Caspi et al. (Biol. Psychiatry 57 (2005)1117–1127) who found association between schizophrenia/schizophreniform disorder and homozygosity at the high activity Val variant of rs4680. The results of our study are discussed in the context of previous findings, suggesting the involvement of COMT polymorphisms in the association between cannabis use and schizophrenia as well as the existence of additional factors mediating this association. However, further research is needed to confirm the COMT–cannabis interaction.

Possible effects of synaptic imbalances on oligodendrocyte-axonic interactions in schizophrenia: a hypothetical model.

A model of glial–neuronal interactions is proposed that could be explanatory for the demyelination identified in brains with schizophrenia. It is based on two hypotheses: (1) that glia–neuron systems are functionally viable and important for normal brain function, and (2) that disruption of this postulated function disturbs the glial categorization function, as shown by formal analysis. According to this model, in schizophrenia receptors on astrocytes in glial–neuronal synaptic units are not functional, loosing their modulatory influence on synaptic neurotransmission. Hence, an unconstrained neurotransmission flux occurs that hyperactivates the axon and floods the cognate receptors of neurotransmitters on oligodendrocytes. The excess of neurotransmitters may have a toxic effect on oligodendrocytes and myelin, causing demyelination. In parallel, an increasing impairment of axons may disconnect neuronal networks. It is formally shown how oligodendrocytes normally categorize axonic information processing via their processes. Demyelination decomposes the oligodendrocyte–axonic system making it incapable to generate categories of information. This incoherence may be responsible for symptoms of disorganization in schizophrenia, such as thought disorder, inappropriate affect and incommunicable motor behavior. In parallel, the loss of oligodendrocytes affects gap junctions in the panglial syncytium, presumably responsible for memory impairment in schizophrenia.

New Perspectives On Gene-Environment Interactions In Schizophrenia

We review the salient recent findings on gene-environment interaction in schizophrenia. The issue of cognitive impairment and metabolic risks in modulating pharmacological treatment responses remain a challenge. The intriguing nature-nurture diathesis is discussed in light of recent breakthroughs in genetic studies from genome association scan methodology and epigenomics. Stem-cell driven neurogenesis offers fresh paradigm to unravel nature-narture interaction. We highlight the relevance of genetics towards resolving Krapaelian dichotomy of classification in schizoaffective disorder at the cross-roads of psychosis and affective disorders. We envisage that future advances in Pharmaco-genomics, Bioinformatics will catalyse the applicaton of personalized medicine in practice of clinical psychiatry.

Dysfunctional Brain Networks and Genetic Risk for Schizophrenia: Specific Neurotransmitter Systems

Multiple neurotransmitter circuits are disturbed in schizophrenia, and the dopamine hypothesis of schizophrenia prevails as the hypothesis with most empirical support. On the other hand, schizophrenia is highly heritable with a pattern consistent with both common and rare allelic variants and gene × environment interaction. Advances in the field of neuroimaging have expanded our knowledge of intermediate phenotypes, the neurobiological processes that convey the risk from the genes to the complex phenotype. In this article, we review the recent and continuously accumulating evidence from in vivo imaging studies aiming at characterizing neurochemical intermediate phenotypes of schizophrenia. Dopaminergic alterations in schizophrenia are shared by individuals at genetic risk who do not express the illness, suggesting a "dopamine hypothesis of schizophrenia vulnerability." This hypothesis has the potential to help us better understand the dopaminergic dysfunction in the context of the complex pathophysiological process leading to schizophrenia. In the future, neurotransmitter imaging studies should investigate the gene × environment interaction in schizophrenia, and try to identify neurobiological correlates of heightened sensitivity to environmental stressors (e.g., cannabis, childhood trauma, and other psychosocial stress) in genetically vulnerable individuals.

Xenobiotic Metabolizing and Transporter Genes: Gene–Gene Interactions in Schizophrenia and Related Disorders

In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders. A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction. A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004). Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia.

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry

Introduction: Dysbindin (DTNBP1) is a widely-studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity. Method: Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent-offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene-gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. Results: No association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pairwise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pairwise comparisons. Conclusions: Our results, based on one of the largest sample of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions.

Emotion–cognition interactions in schizophrenia

Objectives. Negative emotion exerts a considerable influence on cognitive processes. This may have clinical implications in mental illnesses, such as schizophrenia, where negative emotions often prevail. Experimentally this influence can be studied by using olfactory emotion induction. Methods. Fourteen schizophrenia patients and 14 healthy volunteers were investigated with functional magnetic resonance imaging with respect to the neural correlates of emotion–cognition interactions. Emotion was induced by odorants during an n-back working memory task. Results. Similar detrimental effects of negative stimulation on working memory performance were observed in patients and control subjects. Among the neural correlates modulating this interaction a decreased activation emerged in patients in the anterior cingulate and the medial superior frontal cortex and increased activation in the medial orbitofrontal and middle frontal area. Conclusions. During emotion–cognition interaction hypoactivations were found in regions crucial for the monitoring/control of ongoing processes but also for emotion regulation. Decreased activations may reflect failure to adapt to higher task requirements. In contrast, increased activations could be indicative of a greater emotional response and irritation induced by the odour. These patterns may represent the neural correlates of an inefficient control of emotional influences on cognitive processes in patients with schizophrenia.

Elevated plasma γ-aminobutyrate/glutamate ratio and responses to risperidone antipsychotic treatment in schizophrenia

Background γ-aminobutyrate (GABA) and Glutamate (Glu) are respectively two major inhibitory and excitatory neurotransmitters in the central nervous system and recent theories propose that both of their signaling complexes are compromised in patients with schizophrenia. Methods The changes in plasma GABA, Glu and GABA/Glu ratio in schizophrenia have been studied and may be potential clinical markers. Here, we examined if plasma GABA, Glu and GABA/Glu ratio are altered in 32 schizophrenics, including a comprehensive investigation of their involvements with clinical course of a 6-week risperidone antipsychotic treatment. Results Plasma levels of GABA and Glu were significantly lower in patients than in controls, while plasma GABA/Glu ratio was significantly elevated. During treatment, a non-significant further decrease of plasma GABA, a significant increase of plasma Glu and a significant reduction of plasma GABA/Glu ratio were observed. The ratio returned to the control level at week 6 even though concentrations of GABA and Glu were still distant from normal. After the Bonferroni correction, partial correlation analyses showed that plasma GABA and GABA/Glu ratio were positively correlated with the dose of risperidone and plasma concentration of 9-hydroxyrisperidone. The reduction of plasma GABA/Glu ratio was positively correlated with the improvement of activation symptom cluster. Conclusions The elevated plasma GABA/Glu ratio reinforces the idea of an abnormal GABA-Glu interaction in schizophrenia. The ratio may be a good peripheral state-like marker in schizophrenia research.

Verbal Fluency in Schizophrenia

Verbal fluency is impaired in patients with schizophrenia, but the association with other cognitive domains remains unclear. Forty-seven patients with schizophrenia (DSM-IV) and 47 controls matched by age, gender, years of education, and vocabulary (Wechsler Adult Intelligence Scale-III) were assessed in terms of sociodemographic, clinical, and cognitive variables. Healthy controls performed significantly better than patients with schizophrenia in all cognitive measures. However, the way these cognitive domains were related differed across groups. Semantic fluency (SF) and phonological fluency (PF) were predicted by working memory (WM) in patients with schizophrenia, whereas the predictor in the healthy controls was processing speed (PS). Moreover, after dividing the sample of patients according to their performance on fluency tests, we found that a worse performance on SF or PF was predicted by WM. However, for patients with a better performance on fluency, the pattern was similar to that of healthy controls. Cognition may show a different pattern of interaction in schizophrenia, with less impaired patients showing a closer pattern to healthy controls. Therefore, we suggest that, depending on the severity of cognitive deficits, performance on neuropsychological tests may not reflect the same underlying mechanisms.

"Splitting of the Mind" Revisited: Recent Neuroimaging Evidence for Functional Dysconnection in Schizophrenia and Its Relation to Symptoms

"Splitting of the Mind" Revisited: Recent Neuroimaging Evidence for Functional Dysconnection in Schizophrenia and Its Relation to Symptoms

SOCIAL COGNITION AND FUNCTIONAL OUTCOME AS SEPARATE DOMAINS IN SCHIZOPHRENIA

Background: Deficits in social cognition are recognised as an important feature of schizophrenia, mainly due to their close association with poor functional outcome. Impaired functioning in the domains of processing of emotions and interpretation of behaviour of others in the social milieu appears to impact functional outcome in individuals with schizophrenia. Impairments in cognition generally cooccur in these individuals and the magnitudes of deficits in social cognition and cognition are usually strongly associated. Furthermore, whereas cognitive deficits reportedly account for 10%-40% of the variance in functional outcome, social cognition has been shown to have a unique relationship to functional outcome, beyond that of cognitive function. In otherwords, social cognitionmay be amediating factor through which cognition impacts functional outcome. However, both social cognition and functional outcome are broad constructs encompassing multiple abilities. The fact that there is a wide range of measures used to test the above domains further complicates an understanding of the association between social cognition and functional outcome. The purpose of this study was to investigate the factorial validity of social cognitive constructs against that of functional outcome in schizophrenia. Methods: The subjects were 103 individuals with schizophrenia. Facial Emotion Identification Test (FEIT), the Facial Emotion Discrimination Test (FEDT), the Social Cue Recognition Test (SCRT) and the Situational Features Recognition Test (SFRT) were used as measures of social cognition. Cognitive tests were chosen in order to assess a wide range of cognitive domains and were consistent with batteries generally used in the schizophrenia literature. Functional outcome was assessed using two measures: the Quality of Life Scale (QLS) and the Social Functioning Scale (SFS). The Assessment of Interpersonal Problem Solving (AIPPS) scale, which consists of three subscales, was used as a measure of social problem solving. Symptoms were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Results: Using a Principal Component Analysis (PCA) with varimax rotation all social cognitive tasks (i.e. FAIT, FADT, SCRT and SFRT) loaded on factor 1 (SOC COG), all three AIPPS sub-scales loaded on factor 2 (SOCPROBLEM), andbothSFS andQLS loadedon factor 3 (SOC FUNCTION). SOC COG was significantly associated with cognition (r=.54, p<0.001) and with positive (r=-.28, p<0.01) and negative symptoms (r=-.23, p<0.5). SOC PROBLEM was associated with positive (r=-.22, p<0.05) andnegative symptoms (r=-.26, p<0.05) andSOCFUNCTIONwas significantlyassociatedwithpositive (r=-.47, p<0.001) and negative symptoms (r=-.54, p<0.001). Discussion: The factor analysis clearly suggests that social cognition and social functioning are separate constructs. Interestingly a measure of social problem solving that has been at times considered a measure of functioning was differentiated from both social cognition and social functioning. Social cognition was the only factor that was significantly associated with cognition suggesting cognitive underpinning to social perception, social knowledge, and the ability to recognise affect in others. Further, all three factors correlated with both positive and negative symptoms suggesting that interpretation and evaluation of events in the social environment as well as social interactions in schizophrenia may depend on the level of psychotic symptoms.

Effect of antipsychotic treatment on Insulin-like Growth Factor-1 and cortisol in schizophrenia: A longitudinal study

Neurodevelopmental pathogenesis of schizophrenia might be mediated by abnormalities in Insulin-like Growth Factor-1 (IGF-1). Developmental disturbances like obstetric complications, by themselves, as well as through the resultant hypercortisolemia due to hypothalamic–pituitary–adrenal (HPA) axis hyperactivity, can lead to deficient IGF-1 level. The relevance of IGF-1–Cortisol interactions in schizophrenia, especially in the context of antipsychotic treatment, is yet to be explored. In this study, thirty-three antipsychotic-naïve schizophrenia patients (13-men) were examined for serum IGF-1 and cortisol levels at baseline and after 3 months of antipsychotic treatment. For baseline analyses, the patients were compared with 33 healthy controls matched for age, sex, socio-economic status, and physical activity. Symptoms were assessed using Scale for Assessment of Positive Symptoms (SAPS) and Scale for Assessment of Negative Symptoms (SANS). At baseline, schizophrenia patients had significantly lower levels of IGF-1 [ t = 4.6; p < 0.0001] and higher levels of cortisol [ t = 3.9; p = 0.0002] in comparison with healthy controls. Following treatment, IGF-1 level increased significantly [ t = 4.5; p < 0.0001] whereas cortisol decreased significantly [ t = 2.5; p = 0.02] in patients. There was a significant positive correlation between magnitude of increase in IGF-1 level and the magnitude of reduction in cortisol level [ r = 0.52; p = 0.002]. Also, the greater the increase in IGF-1 the greater was the reduction in SAPS score [ r = 0.39; p = 0.02]. Our study findings demonstrate that antipsychotic treatment can result in significant elevation of serum IGF-1 possibly mediated by reduction in cortisol levels. These observations suggest a possible link between HPA axis abnormalities and IGF-1 deficits in the neurodevelopmental pathogenesis of schizophrenia.

No association between EGR gene family polymorphisms and schizophrenia in the Chinese population

Early growth response (EGR) genes are thought to have a role in the pathogenesis of schizophrenia because of their conserved DNA binding domain and biologically activity in neuronal plasticity. This zinc-finger motif could influence gene post-translational modification and expression. The multigenetic association model, using markers in genes of similar or antagonistic biological effects within a signal pathway or gene family, might be more appropriate to this aspect of the schizophrenia hypothesis than the single gene strategy. In this study we investigated the role of EGR1, EGR2, EGR3 and EGR4 within the EGR family. Taqman technology was used to examine 12 single nucleotide polymorphisms (SNPs) covering these four genes in 2044 Chinese Han subjects. Case–control analyses were performed to detect association of these 4 genes with schizophrenia and multifactor dimensionality reduction (MDR) analysis was employed to examine their potential gene–gene interaction in schizophrenia. Neither allelic nor genotypic single-locus tests revealed any significant association between EGR1–4 and the risk of schizophrenia nor was any such association found with regard to interaction within EGR1–4 ( p min = 0.623, CV Consistency = 10/10). We concluded that although multiple candidate genes are involved in schizophrenogenic development, the EGR family may not play a major role in schizophrenia susceptibility in the Chinese Han population.

A reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case–control and family-based sample of German ancestry

BackgroundDysbindin (DTNBP1) is a widely studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity. MethodSix hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent–offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene–gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT. ResultsNo association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pair-wise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pair-wise comparisons. ConclusionsOur results, based on one of the largest samples of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions.