Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction

Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited.     

Genetic variation of the mitochondrial complex I subunit NDUFV2 and Parkinson's disease

NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), encoding a subunit of mitochondrial complex I, is a candidate gene for several neuronal diseases; schizophrenia, bipolar disorder and Parkinson disease (PD). We screened the entire coding region of NDUFV2 in 33 familial PD patients of North African Arab-Berber ethnicity in which all known genetic forms of PD had been excluded. We detected one novel substitution p.K209R (c.626A > G) in one PD proband. Segregation analysis within the family is inconclusive due to small sample size, but consistent with an autosomal dominant mode of inheritance. Subsequent screening of this mutation in ethnically matched sporadic PD patients (n = 238) and controls (n = 371) identified p.K209R in one additional patient. The clinical features of the mutation carriers revealed a mild form of parkinsonism with a prognosis similar to idiopathic PD. Our findings suggest further studies addressing the role of NDUFV2 variation in PD may be warranted.     

Self-rated and performance-based empathy in schizophrenia: The impact of cognitive deficits

People may be much less empathic than they think they are. It is not clear whether patients with schizophrenia who have impaired empathic abilities also exhibit diminished ability to accurately appraise their own such skills. The present study aimed to examine: (a) the accuracy of self-appraisal of empathy and (b) the impact of specific cognitive functions on both self-rated and performance-based empathy in schizophrenia patients and healthy volunteers. Self-reported empathy and performance-based empathy were assessed in 52 chronic patients with schizophrenia and 45 matched healthy participants with the empathy quotient and the empathy score in the Faux Pas test, respectively. Neuropsychological functioning and symptom severity were also assessed. No significant correlations between self-reported and performance-based empathy scores were found in patients, whereas these correlations were significant and positive in the control group, with the exception of Faux Pas recognition. Cognitive deficits, specifically in processing speed and theory of mind, negatively affected performance-based but not self-rated empathy in schizophrenia. Patients with less negative and more positive symptoms and lower set shifting ability reported higher empathic abilities. Self-reported empathy and empathic abilities do not show a simple relationship. Our findings highlight a double deficit related to empathic responding in schizophrenia: diminished performance associated with cognitive deficits and inaccurate self-appraisal of empathic abilities.     

Depression and cognitive deficits in geriatric schizophrenia

Objective

Past reports have found patients with comorbid depression and schizophrenia spectrum disorders exhibit greater deficits in memory and attention compared to schizophrenia spectrum disorder patients without depressive symptoms. However, in contrast to younger schizophrenia patients, the few past studies using cognitive screens to examine the relationship between depression and cognition in inpatient geriatric schizophrenia have found that depressive symptomatology was associated with relatively enhanced cognitive performance. In the current study we examined the relationship between depressive symptoms and cognitive deficits in geriatric schizophrenia spectrum disorder patients (n = 71; mean age = 63.7) on an acute psychiatric inpatient service.

Method

Patients completed a battery of cognitive tests assessing memory, attention and global cognition. Symptom severity was assessed via the PANSS and Calgary Depression Scale for Schizophrenia.

Results

Results revealed that geriatric patients' depression severity predicted enhancement of their attentional and verbal memory performance. Patients' global cognitive functioning and adaptive functioning were not associated with their depression severity.

Conclusion

Contrary to patterns typically seen in younger patients and non-patient groups, increasing depression severity is associated with enhancement of memory and attention in geriatric schizophrenia spectrum disorder patients. Also, diverging from younger samples, depression severity was unassociated with patients adaptive and global cognitive functioning.     

Executive attention deficits in schizophrenia: Putative mandatory and differential cognitive pathology domains in medicated schizophrenia patients

Executive attention (EA) is a core-construct of working memory (WM) capacity. EA performance is directly related to dorsolateral prefrontal cortex (DLPFC) activation, a neural mechanism that is dysfunctional in schizophrenia. We examined the differences in particular types of EA failure in schizophrenia patients and healthy controls. We evaluated executive attention in 60 medicated schizophrenia patients and 60 matched healthy individuals. We used a standard WM task, a verbal n-Back task, to measure executive attention (WM accuracy). Our standard-version WM task (control block, 10 min long) was designed to examine baseline executive attention function and was followed by one out of three different experimental blocks (revised n-Back tasks). Baseline executive attention performance was significantly related to psychosis severity and functional capacity in the psychiatric group. In both healthy and psychiatric groups, experimental-block conditions revealed that domain-general recall had a differential effect on WM scores, and was related to the patient's clinical condition. Only in the psychiatric group domain-specific recall impairments were mandatory, most severe, and independent of baseline WM scores. The results revealed the importance of domain-general recall WM scores in the evaluation of executive attention deficits in patients and controls. Disruption in domain-specific recall may represent a specifier of cognitive impairment in schizophrenia spectrum disorders.     

Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with personality traits in healthy individuals

BACKGROUND: Differences in personality traits have long been acknowledged as potential risk factors in developing psychiatric disorders. Lately, several susceptibility genes of different psychiatric disorders have been linked to personality traits. This has not been done for schizophrenia yet. Neuregulin1 has been repeatedly shown to be associated with schizophrenia and is involved in numerous neurodevelopmental functions such as neuronal migration and myelination. The impact of this gene might also modulate personality traits in healthy subjects. METHODS: The NRG1 status of 523 healthy subjects was determined with a single nucleotide polymorphism (SNP8NRG221533) which has been described as a tagging marker being part of the core at-risk haplotype for schizophrenia. Genotype was correlated with personality traits using the NEO-FFI questionnaire. RESULTS: Subjects with the NRG1 risk allele scored higher on neuroticism (p<.05) and lower on conscientiousness (p<.05). Further, interactions of genotype by gender for extraversion (p<.05), openness (p<.05) and conscientiousness (p<.05) were found with men carrying the risk allele scoring the lowest. CONCLUSIONS: The data indicate that the NRG1 gene which has found to be associated with schizophrenia may also influence personality differences in healthy subjects.     

Meta-analysis of association between genetic variants in COMT and schizophrenia: An update

A common functional polymorphism, Val108/158Met (rs4680), and haplotypes rs737865–rs4680–rs165599 in the Catechol-O-methyltransferase gene (COMT) have been extensively examined for association to schizophrenia; however, results of replication studies have been inconsistent. The aim of this study was to comprehensively evaluate the genetic risk of COMT for schizophrenia.First, we performed a mutation scan to detect the existence of potent functional variants in the 5′-flanking and exon regions. Second, we conducted a gene-based case–control study between tagging single nucleotide polymorphisms (SNPs) in COMT [19 SNPs including six possible functional SNPs (rs2075507, rs737865, rs4680, rs165599, rs165849)] and schizophrenia in large Japanese samples (schizophrenics 1118, controls 1100). Lastly, we carried out a meta-analysis of 5 functional SNPs and haplotypes (rs737865–rs4680–rs165599).No novel functional variant was detected in the mutation scan. There is no association between these tagging SNPs in COMT and Japanese schizophrenia. In this updated meta-analysis, no evidence was found for an association between Val108/158Met polymorphisms, rs6267, rs165599, and haplotypes (rs7378655–rs4680–rs165599) and schizophrenia, although rs2075507 and rs737865 showed trends for significance in allele-wise analyses (P = 0.039 in a multiplicative model, P = 0.025 in a recessive model for rs2075507, P = 0.018 in a dominant model for rs737865, uncorrected). This significance did not remain, however, after correcting the P-values using a false discovery rate controlling procedure.Our results suggest that the COMT is unlikely to contribute to susceptibility to schizophrenia.     

Clinical impact of recently detected susceptibility genes for schizophrenia

After years of frustration, the search for genes impacting on schizophrenia is now undergoing some exciting developments. Several proposals of susceptibility genes have been able to be supported by replications. Thus, there are now at least three very strong candidates: the gene for dysbindin (DTNBP1), the gene for neuregulin-1 (NRG1), and a less well-understood gene locus, G72/G30, which are likely to influence manifestations of schizophrenia. Other "hot" candidates such as the disrupted-in-schizophrenia 1 gene (DISC1) and the gene coding for protein kinase B (AKT1) might also prove to be susceptibility genes in the next future. The clinical implications of these findings are not yet fully visible. However, some first insights are possible: most of the genetic findings lack diagnostic specificity, and are also reproduced in bipolar disorder. Strong associations are also obtained on a symptomatic level, not only on a diagnostic level. The pathophysiological role of these hot candidate genes is currently under intensive study.     

Reappraisal of the role of the DRD3 gene in essential tremor

OBJECTIVES: Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET. METHODS: The role of 312G>A DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals. RESULTS: Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course. CONCLUSIONS: Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.     

Association analyses of the DAOA/G30 and d-amino-acid oxidase genes in schizophrenia: Further evidence for a role in schizophrenia

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed d-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the d-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes d-serine, a potent activator of the N-methyl-d-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.     

Effects of MK-801 on D1 dopamine receptor-mediated immediate early gene expression in the dopamine-depleted striatum

Previous work indicates that intrastriatal administration of MK-801 does not completely block D1 agonist-induced gene expression in dopamine-depleted rats. The present study examined the effects of systemic MK-801 on such gene expression. A low dose of MK-801 did not affect induction of c-fos or zif268. A high dose completely blocked induction of c-fos, but only slightly suppressed zif268. The data suggest that NMDA receptor activity may not always be necessary for D1-induced gene expression.     

A case–control association study between the CYP3A4 and CYP3A5 genes and schizophrenia in the Chinese Han population

In this study, variants of two genes coding for cytochrome P450 enzyme (CYP3A4 and CYP3A5) were analysed in a case–control sample using 398 schizophrenic patients and 391 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of CYP3A4 and CYP3A5 gene polymorphisms between the groups. However, the two-marker haplotypes covering components CYP3A41G and CYP3A53 were observed to be significantly associated with schizophrenia (corrected global p = 0.0009). In addition, we identified one common risk haplotype, G/G (present in 59.5% of the general population). The results suggest that CYP3A4 and CYP3A5 might play a role in genetic susceptibility to schizophrenia. However, confirmatory studies in independent samples are needed.     

ARVCF single marker and haplotypic association with schizophrenia

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3′ downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3′ region of the ARVCF gene.     

Phenotypic variation between parent-offspring trios and non-trios in genetic studies of schizophrenia

BACKGROUND: Phenotypic differences between parent-offspring trios and non-trios have been reported for various psychiatric disorders, and it has been suggested that this may make comparisons of case-control and family-based results for gene-disease association studies inappropriate. AIMS: To compare phenotypes between trios and non-trios with schizophrenia, and explore possible reasons for differences observed. METHOD: Phenotypes were compared between trios (n=75) and non-trios (n=424) collected as part of a case-control study. RESULTS: Differences were observed for most phenotypes investigated, although all were eliminated after adjusting for confounding. CONCLUSIONS: Confounding, genetic heterogeneity or selection bias could result in differences in case-control and family-based results. However as we discuss, where adequately designed case-control studies are used, gene-disease association results would be incomparable between family-based and case-control studies only if genetic heterogeneity was present. These results do not support the presence of such genetic heterogeneity in schizophrenia.     

The relevance of cognitive,clinical and premorbid variables in predicting functional outcome for individuals with first-episode psychosis: A 3 year longitudinal study

Real-world functional deficits are common and persistent in individuals with psychosis. Cognitive deficits have been shown to compromise functioning. We aimed to study the predictive values of premorbid, sociodemographic, and baseline clinical and neurocognitive factors on long-term functional outcome for individuals with first episode non-affective psychosis. We failed to demonstrate a significant relationship between cognitive deficits at baseline and functional disability at 3 year follow-up. Diagnosis of schizophrenia (OR=2.457, p=0.011), shorter education (OR=1.177, p=0.005) and poor premorbid social adjustment (OR=1.628, p=0.013) emerged as the strongest predictors for the 114 subjects (56%) that exhibited functional disability at 3-year follow-up. A considerable proportion of the variance in functioning (74% at 1 year and 77% at 3 year) remained unexplained by baseline variables. The set of variables that predicted functional outcome at medium- (1 year) and long-term (3 years) differed. In conclusion, the length of follow-up influenced the relationship between baseline variables and functional outcome. A substantial proportion of the variance in function was not explained by these variables and therefore the influence of other factors warrants further investigation. The data support the notion that premorbid social adjustment is an important aspect in functional outcome over the course of the illness.     

Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population

Disrupted-in-Schizophrenia-1 (DISC1) has first been identified as a candidate gene for schizophrenia through study of a Scottish family with a balanced (1; 11) (q42.1; q14.3) translocation. Lots of linkage and association studies supported DISC1 as a risk factor for schizophrenia. In this study, we genotyped three SNPs in DISC1 using a set of Han Chinese samples of 560 schizophrenics and 576 controls. No positive association was detected in the whole samples but analysis of allele frequencies in female samples showed weak association between SNP rs2295959 and the disease (chi(2)=6.188, P=0.0135, OR=0.728, 95% CI=0.567-0.935). Our results provide further evidence for sex difference for the effect of the gene on the aetiology of schizophrenia. Our findings also would encourage further studies, particularly family-based association studies with larger samples, to analyze the association between DISC1 and schizophrenia.     

Association study of HLA-A gene and schizophrenia in Han Chinese from Taiwan

Dysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.     

Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics

Schizophrenia is a severe mental illness affecting around 1% of adults with a high degree of morbidity and mortality. Affected individuals are at increased risk for unemployment, handicap, obesity, diabetes mellitus, hearth attack and suicide. Antipsychotic drugs are the best treatment for this disease, but about 20% of patients display drug resistance, or refractoriness, and may receive a special neuroleptic named Clozapine. Despite its superiority from other neuroleptics, only 30–60% of drug-resistant patients are responsive to clozapine. Clozapine’s action results from interactions between dopaminergic and serotonergic neurotransmitter systems and since clozapine appears to exert its effect strongly through the serotonergic systems, alterations in serotonin synaptic levels may influence antipsychotic response. The serotonin transporter (5-HTT) is responsible for pre-synaptic re-uptake of serotonin, making this transporter a logical candidate gene for prediction of clozapine response and to increase understanding about mechanisms of refractoriness. Therefore, we investigated the influence of two polymorphisms in the 5-HTT gene (HTTLPR/rs25531 and VNTR Stin2) in clozapine response in a sample of 116 schizophrenic individuals of European descent from South-Brazil. Significant differences between responders and non-responders to clozapine were observed for the HTTLPR/rs25531 polymorphism. Nonresponders to clozapine showed a higher frequency of S′-allele (P = 0.01) and also were more likely to be S′/S′ homozygous or S′/L′ heterozygous than those who did respond (P = 0.04). After controlling for confounding variables, logistic regression analyses confirmed this association (OR = 3.15; 95% CI: 1.13–8.80). The observed association suggests that increased availability of extracellular serotonin concentrations at all synapses may reduce clozapine effect.