Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis.

BACKGROUND: The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation. METHODS: We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter. RESULTS: In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume. LIMITATIONS: The sample size is modest given that a low-frequency variant was being examined. CONCLUSION: The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.

De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.

Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.

Are metabolic indices different between drug-naïve first-episode psychosis patients and healthy controls?

OBJECTIVE: To compare glucose and lipid metabolism parameters between drug-naïve first-episode psychosis (FEP) patients with a diagnosis of schizophrenia spectrum disorder and healthy controls matched for age, ethnicity, and gender. METHOD: Baseline evaluations of fasting glucose and lipid metabolism parameters and the oral glucose tolerance test were performed with FEP patients (n=38), having no more than 10 days of cumulative exposure to antipsychotic medication, and normal community controls (n=36). Analysis of variance (ANOVA) was conducted to examine between group differences. RESULTS: FEP patients did not show a higher prevalence of the precursors to diabetes (impaired fasting glucose, impaired glucose tolerance, insulin resistance), and no significant difference in beta-cell function or lipid profile measures, compared to healthy controls. FEP patients showed a higher waist to hip ratio compared to controls. CONCLUSIONS: FEP patients having a schizophrenia spectrum disorder do not differ from healthy controls, in their baseline measures of glucose and lipid metabolites, nor in the prevalence of diabetes or its precursors, before (or close to) the onset of antipsychotic treatment.

No association between the DRD3 Ser9Gly polymorphism and schizophrenia.

OBJECTIVE: To investigate the association between a Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia. METHODS: 408 schizophrenic patients and 172 control subjects were compared with regard to their DRD3 Ser9Gly genotypic and allelic frequencies. In addition, we carried out a family-based association study including 183 pedigrees (472 subjects) using the transmission disequilibrium test (TDT). RESULTS: No significant differences of genotype or homozygosity distribution were identified between patients and controls. When patients were stratified according to gender, response to treatment, age at onset, no significant differences were observed. Neither allele A (Ser), or G (Gly) were preferentially transmitted from parents to affected offspring. CONCLUSION: The hypothesis that the DRD3 Ser9Gly polymorphism plays a predisposing role in schizophrenia is not supported by this study.

Dopamine transporter 3'-UTR VNTR genotype and ADHD: a pharmaco-behavioural genetic study with methylphenidate.

We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

Validation of the English and French versions of the Community Assessment of Psychic Experiences (CAPE) with a Montreal community sample.

OBJECTIVE: The aim of this study was to examine the reliability, validity and factor structure of the Community Assessment of Psychic Experiences (CAPE), a 42-item self-report questionnaire. We analyzed the internal consistency of the CAPE to determine whether the 3-factor structure (positive, negative and depressive symptoms) found by the CAPE authors would also be found in our sample. METHOD: A sample of 2275 individuals from the general community in the Montreal area completed the questionnaire in either French or English. RESULTS: The internal consistencies of the original three subscales were good and the confirmatory factor models had a good fit. The exploratory factor analysis suggested a 3-5-factor solution, without improving the alternative factor structures. The 4-factor solution separated positive symptoms into factors we called 'bizarre positive symptoms' and 'social delusions', and the 5-factor solution separated positive symptoms further and included a 'popular psychic beliefs' factor. Results suggest that the scalability might be improved by shortening the original questionnaire to 23 items with the same 3 original scales. CONCLUSION: We support the internal consistency of the CAPE. Although alternative scaling (4 and 5 factors) did not improve the model fit, researchers interested in distinguishing 3 factors of positive symptoms could find utility in these two new scales. Finally, reducing the number of CAPE items could be useful for shorter surveys. Future studies should test the implications of these suggestions.

Polygenic Risk Score associated with specific symptom dimensions in first-episode psychosis.

Recent Genome-Wide Association Studies (GWAS) have provided evidence for the involvement of a number of genetic variants in schizophrenia (SCZ). The objective of the current study was to examine the association between these variants and symptom dimensions, evaluated prospectively over a period of 24months, in a clinically well-characterized sample of individuals (n=241) with first-episode psychosis (FEP). The genetic variants were analyzed collectively as captured through a Polygenic Risk Score (PRS), calculated for each individual. At each evaluation time point (baseline, 1, 2, 6 and 24months), correlation analysis was conducted with PRS and symptom dimension scores assessed by the Positive and Negative Syndrome Scale (PANSS). We also examined the association of PRS with global symptom rating, depression, anxiety, social and occupational functioning as measured by widely used and well validated scales. At baseline, significant positive correlation was observed between PRS and the general psychopathology dimension of the PANSS but no associations were observed with the positive or negative symptom dimensions. Anxiety, assessed using the Hamilton Anxiety Rating Scale, was also significantly correlated with the PRS. No significant correlation was observed with other symptom dimensions or with the PANSS score at the later evaluations. These results provide novel evidence of an association between general psychopathology and PRS in young people with first episode psychosis. They also demonstrate that it is important to note the dynamic changes of symptoms over time when trying to refine the relationship between genetic factors and phenotypes.

Association study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.

BACKGROUND: Brahma (BRM) is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG) repeat, the only known polymorphism in the coding region of the gene (SMARCA2). We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis. RESULTS: Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289) and unaffected controls (n = 273) in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin. CONCLUSION: Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.

CAA insertion polymorphism in the 3'UTR of Nogo gene on 2p14 is not associated with schizophrenia.

The Nogo gene was putatively implicated in schizophrenia based on gene expression and genetic association data. In this study, we attempt to replicate the possible association of the CAA insertion and a nearby TATC deletion with schizophrenia in 204 complete and incomplete triads and in a sample of 462 unrelated cases and 153 controls, all of Caucasian origin. Our genotyping results indicated that neither the trinucleotide insertion polymorphism (CAAins; 43.4% vs. 41.8%, p>0.5) nor the polymorphism-TATC deletion (TATCdel; 49.8% vs. 49.3%, p>0.1) allele frequency is significantly different in patients compared to controls. The homozygous CAAins frequency is not significantly different between patients and controls either (18.0% vs. 15.0%, chi2=0.985, p>0.1). Furthermore, neither CAAins/TATCdel individually, nor the haplotype carrying both CAAins and TATCdel is preferentially transmitted to affected offspring.

TCF4 gene polymorphism and cognitive performance in patients with first episode psychosis.

BACKGROUND: Single nucleotide polymorphisms in TCF4 gene have been consistently associated with schizophrenia in genome wide association studies, including the C allele of rs9960767. However, its exact role in modulating the schizophrenia phenotype is not known. AIMS: To comprehensively investigate the relationship between rs9960767 risk allele (C) of TCF4 and cognitive performance in patients with first episode psychosis (FEP). METHODS: 173 patients with FEP received a comprehensive neurocognitive evaluation and were genotyped for rs9960767. Carriers of the risk allele (CA/CC) were compared to non-carriers (AA) using Multivariate Analysis of Covariance MANCOVA. Ethnicity, negative symptoms and substance abuse were included as covariates. RESULTS: Carriers of the risk allele had a statistically significant lower performance in the cognitive domain of Reasoning/Problem-Solving compared to non-carriers (F1,172=4.4, p=.038). There were no significant genotype effects on the other cognitive domains or general cognition. This effect on the Reasoning/Problem-Solving domain remained significant even when controlling for IQ (F1,172=4.3, p=.039). CONCLUSIONS: rs9960767 (C) of TCF4 appears to be associated with neurocognitive deficits in the Reasoning/Problem-Solving cognitive domain, in patients with FEP. A confirmation of this finding in a larger sample and including other TCF4 polymorphisms will be needed to gain further validity of this result.

Association between schizophrenia and genetic variation in DCC: a case-control study.

Schizophrenia is a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted in dcc-heterozygous mice show that DCC plays a critical role in the developmental organization of the mesocorticolimbic dopamine (DA) circuitry. Furthermore we have shown that reduced expression of DCC during development and/or throughout life confers resilience to the development of schizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whether DCC may contribute to the risk of schizophrenia. We examined single nucleotide polymorphisms (SNPs) located in the DCC gene for association with schizophrenia using a case-control sample consisting of 556 unrelated schizophrenic patients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated with schizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (χ(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point at DCC as a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility to schizophrenia.

Neural markers of remission in first-episode schizophrenia: a volumetric neuroimaging study of the hippocampus and amygdala.

OBJECTIVE: The temporolimbic region has been implicated in the pathophysiology in schizophrenia. More specifically, significantly smaller hippocampal volumes but not amygdala volumes have been identified at onset in first-episode schizophrenia (FES) patients. However, volumetric differences (namely, in the hippocampus) exhibit an ambiguous relationship with long-term outcome. So, we examined the relationship between hippocampus and amygdala volumes and early remission status. METHODS: We compared hippocampus and amygdala volumes between 40 non-remitted and 17 remitted FES patients and 57 healthy controls. Amygdala and hippocampus were manually traced with the hippocampus additionally segmented into three parts: body, head, and tail. Remission was defined as mild or less on both positive and negative symptoms over a period of 6 consecutive months as per the 2005 Remission in Schizophrenia Working Group criteria. RESULTS: A significant [group x structure x side] interaction revealed outcome groups differed in hippocampus tail volumes; significantly on the left (non-remitted=694+/-175 mm(3); remitted=855+/-133 mm(3); p=0.001) with a trend difference on the right (non-remitted=723+/-162 mm(3); remitted=833+/-126 mm(3); p=0.023). Groups did not differ in body, head, or amygdala volumes bi-laterally. CONCLUSIONS: A smaller hippocampal tail volume may represent a neural marker in FES patients who do not achieve early remission after the first 6 months of treatment. The early identification of patients with poor outcome with respect to the hippocampus tail may encourage the search for new, more target-specific, medications in hope of improving outcome and moving us towards a better understanding of the pathophysiology of schizophrenia.

De novo truncating mutation in Kinesin 17 associated with schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. METHODS: As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. RESULTS: Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. CONCLUSIONS: Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.