Sarah Clarke

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.

Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample.

The D‐amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. ( 2002 ); PNAS 99: 13675–13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM‐IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required.

Dysbindin (DTNBP1) and the Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1): Main and Epistatic Gene Effects Are Potential Contributors to Schizophrenia Susceptibility

BACKGROUND The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching. METHODS A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results. RESULTS We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing. CONCLUSIONS Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.

Neurocognition and suicidal behaviour in an Irish population with major psychotic disorders.

OBJECTIVES Although neurocognitive deficits are seen as core to schizophrenia the association between suicidality and neurocognition has received little attention. Our aim was to examine the relationship between neurocognitive variables and suicidal behaviour in patients with schizophrenia and schizoaffective disorder. METHODS Seventy-eight patients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were categorised as either having attempted suicide or not having attempted suicide based on clinical interview and chart review. Attempters and non-attempters were compared on an extensive neuropsychological battery examining pre-morbid and current general cognitive functioning, episodic memory, and executive functioning. RESULTS Suicide attempters tended to out perform non-attempters across all areas of executive functioning, and showed significantly better performances on measures of attention and verbal fluency. After controlling for relevant clinical and demographic variables, the differences between attempters and non-attempters remained significant for measures of attention (F = 4.97, p = 0.03) and verbal fluency (F = 4.28, p = 0.04). CONCLUSION This study adds to existing data that suicide attempters with schizophrenia or schizoaffective disorder may have higher cognitive functioning than non-attempters. In particular, the preservation of higher executive function may influence the ability to initiate and plan suicidal behaviour.

Are deficits in executive sub-processes simply reflecting more general cognitive decline in schizophrenia?

BACKGROUND Schizophrenia is associated with both global and specific cognitive deficits. We sought to investigate whether deficits in executive subcomponents differed in their relationship to global cognitive impairments. METHOD 95 patients were classified according to pre-morbid and current general cognitive ability as having either (a) intact pre-morbid and current general cognitive ability; (b) intact pre-morbid but deteriorated current ability, and (c) deteriorated both pre-morbid and current cognitive ability. All patients completed measures of verbal and spatial working memory, sustained selective attention, attentional set sifting, and inhibitory control. RESULTS Deficits on both measures of working memory were associated with general cognitive ability. None of the attentional control deficits observed were associated with general ability. Further, spatial working memory deficits were also associated with more severe negative symptoms. CONCLUSIONS These results provide further evidence of the discreet nature of attentional deficits in schizophrenia. By contrast, this study suggests that working memory deficits may to some extent index more general cognitive decline. Awareness of such overlap is important for schizophrenia genetics studies where working memory measures has been used to index supposedly discreet aspects of cognitive dysfunction.

Chitinase-3-Like 1 (CHI3L1) Gene and Schizophrenia: Genetic Association and a Potential Functional Mechanism

BACKGROUND Gene expression data and association analyses in two Chinese samples implicate chitinase 3-like 1 (CHI3L1), a cellular survival gene, in schizophrenia susceptibility. METHODS We tested whether the association data are robust to replication in a Caucasian schizophrenia sample and performed a comprehensive investigation of common genetic variation at the locus. RESULTS In a sample of 375 case and 812 control subjects we identified significant association with the same risk allele at the promoter single nucleotide polymorphism (SNP) associated in the original study (rs10399805; p = .018) and with another SNP at intron 7 of CHI3L1 (rs2275351; p = .008). The rs10399805 SNP is located at position -247 and disrupts the C/EBP-AML-1 binding site in the gene promoter; the risk allele is predicted to increase CHI3L1 expression, as has been reported in several postmortem schizophrenia studies. Carriers of the risk variant presented with fewer positive symptoms and relatively spared cognitive performance compared with other schizophrenia patients. CONCLUSIONS These findings support a functional mechanism for involvement of CHI3L1 in schizophrenia susceptibility, possibly contributing to a less severe illness. The associated variants in this study are not well tagged by all Whole-Genome Association (WGA) platforms, suggesting additional genotyping may be necessary despite the imminent availability of WGA data from large SZ samples. Because CHI3L1 may be involved in transmission of stress-induced cellular responses, studies of interaction with known environmental risk factors may also be warranted.

DAOA ARG30LYS and verbal memory function in schizophrenia

LP). The odds ratios and standard errors of Taq1A and 141C I/D for TD were calculated from the individual studies using the ‘metan’ command, with the pooled odds ratio and standard error calculated under the random effects model. The possible effects of ethnicity, age, and gender ratio on heterogeneity among the studies were assessed by meta-regression analysis using the ‘metareg’ command. We tested for publication bias using the ‘metabias’ command. Compared to TD-negative patients, TD-positive patients had a higher A2 allele frequency (P = 0.003), with an effect-size of 1.30 (95% CI: 1.09–1.55), and higher A2/A2 genotype frequency (P = 0.001), with an effect-size of 1.50 (95% CI: 1.17–1.92). The 141C Ins/Del alleles and genotypes were not associated with TD. There was no evidence of heterogeneity among the studies or publication bias for Taq1A or 141C Ins/Del (P > 0.1). Ethnicity, gender ratio, or age did not contribute to the results observed for Taq1A (P > 0.1). Despite heterogeneity amongst studies in terms of TD assessment, results from the present meta-analysis suggest that Taq1A is associated with TD and are in agreement with two of the previous studies. The mixed results in other studies could be attributed to the lower A1 allele frequencies observed in European Caucasians compared to East Asians, as well as to small sample sizes. The results reported here could be affected by potential confounding factors, including tobacco and substance use, antipsychotic dose, and years of antipsychotic exposure, information that was not available for most of the studies. False-positive results from multiple testing are possible, but association between Taq1A and TD from the present metaanalysis would have survived correction for testing two markers. The relatively low OR is consistent with the idea of contributions of multiple genetic variants in complex phenotypes, with DRD3 Ser9Gly as an example of another genetic risk factor for TD. Nonetheless, the present study, the first meta-analysis of DRD2 polymorphisms in TD, encourages further examination of the role of Taq1A in TD.

Do antisaccade deficits in schizophrenia provide evidence of a specific inhibitory function

BACKGROUND Despite its inhibitory control requirements, antisaccade deficits have been consistently associated with working memory impairments in schizophrenia. We investigated whether variance in antisaccade performance could be better accounted for in terms of a specific inhibitory function. METHOD We assessed 48 clinically stable out-patients with schizophrenia on an antisaccade task, as well as on measures of spatial and verbal working memory, sustained selective attention, and a simple motoric go/no-go measure of response inhibition. RESULTS In a stepwise multiple regression analysis, go/no-go task performance accounted for a considerably greater percentage of variance in antisaccade performance (25.3%) than either working memory (8.4%) or sustained selective attention task (9.1%). DISCUSSION We conclude that antisaccade deficits in schizophrenia appear to be better understood in terms of a specific deficit of inhibitory control than in terms of more general difficulties with context maintenance or goal neglect.

Investigation of the apolipoprotein-L (APOL) gene family and schizophrenia using a novel DNA pooling strategy for public database SNPs.

We performed an extensive genetic association study of the six known apolipoprotein-L (APOL) genes and schizophrenia (SZ) using a novel DNA pooling strategy. The APOL genes are both positional and functional candidate genes for SZ. This gene family maps to chromosome 22q12.3, a region implicated by SZ linkage studies as likely to contain one or more SZ susceptibility genes. A recent gene expression study demonstrated up-regulation of APOL1, 2, and 4 in post-mortem brain samples from SZ patients compared to controls in two independent samples. To test for genetic association with SZ, we analyzed 143 SNPs from dbSNP from across the APOL genes in an Irish sample of 219 cases and 231 controls. Of these 143 SNPs, 51 (36%) were polymorphic in our Irish sample and were genotyped using a novel three-stage DNA pooling strategy. This strategy does not require the identification of a heterozygous individual for DNA pooling association analysis and is therefore very efficient when using public database SNPs. We found no evidence to support the hypothesis that genetic variation at the APOL genes contributes to SZ susceptibility in our sample.

Variance in facial recognition performance associated with BDNF in schizophrenia

Deficits in memory are among the most severe cognitive impairments in schizophrenia [Heinrichs and Zakzanis, 1998], and show evidence of familiality [Goldberg et al., 1990; Cannon et al., 2000]. Brain derived neurotrophic factor (BDNF) is a critical element in modulating synaptic changes, such as hippocampal long-term potentiation (LTP), associated with learning and adaptive behaviors in adult animals [Poo, 2001; Tyler et al., 2002]. In the gene coding for BDNF, a frequent polymorphism (VAL66MET; dbSNP: rs6265) has previously been associated with variance in verbal memory recall in schizophrenia [Egan et al., 2003; Dempster et al., 2005; Tan et al., 2005]. Whether this effect for the VAL66MET polymorphism is specific to verbal memory functioning ormay also be associated with variance in visual and spatial memory in schizophrenia is unclear. Based on a control sample, Hariri et al. [2003] reported that the VAL66MET polymorphism was also associated with changes in cortical activation during a visual recognition task using fMRI. We investigatedwhether theBDNFVAL66METpolymorphism was associated with visuo-spatial memory function in schizophrenia. After receiving ethics approval we conducted memory assessments of a subset of our total sample (comprised of 359 cases and 745 controls, all of Irish nationality and ancestry). Inclusion was dependent on patients’ continuing availability and consent, aswell as their being clinically stable, aged between 18 and 60 years, and free from confounding factors such as epilepsy, substance abuse, or acquired brain injury. This subgroup (n1⁄4 91), comprised of 4 MET/MET, 20 MET/VAL, and 67 VAL/VAL carriers, had a mean age of 46.2 years (SD9.3), was comprised primarily of males (75%), and had a predominantly chronic illness history (duration in years 22.3 10.4; range 4–42). Visual spatial memory recall was measured using the paired associate learning task from the Cambridge Automated Test Battery (CANTAB). Recognition memory was measured using the facial recognition memory test from the Wechsler Memory Scale (3rd Edition; WMS-III). Pre-morbid IQ was also ascertained using the Wechsler Test of Adult Reading (WTAR). Controls in our study were obtained through the Irish blood transfusion service and neuropsychological data was not obtainable for these. Consistent with previous reports, BDNF VAL66MET was not associated with risk for schizophrenia in our total case control sample (BDNF MET allele frequency in 359 cases vs. 745 controls (16.7% vs. 16.7%)). When patients were classified on the basis of BDNF genotype (carriers of 1 or 2 copies of the MET alleles vs. homozygous VAL carriers), no differences between genotype groups were observed on demographic variables, pre-morbid IQ or prescribed antipsychotic medication type (typical vs. atypical).MET carriers did not differ from homozygous VAL carriers in visuo-spatial memory performance (F(2,87)1⁄4 0.08;P> 0.05). However, carriers of theMET allele showed significantly poorer performance in immediate facial recognition (F(2,87)1⁄4 6.78; P< 0.05) (Fig. 1). In a regression equation, when the effects of age and pre-morbid IQ (both of which influence memory performance) were partialled out, BDNF genotype explained 7% of the variance in immediate facial recognition in the present sample. Our investigation of BDNF VAL66MET extends previous research by suggesting a role for this polymorphism in mediating facial recognition in schizophrenia. Thispolymorphism has previously been associated with visual recognition memory in healthy controls [Hariri et al., 2003], and explained in terms of the deleterious effects of the MET allele on hippocampal function, which is in turn behaviorally expressed by poorer memory tasks performance. Facial recognition deficits are widely reported in schizophrenia, along with evidence of their familiality [Goldberg et al., 1995; Conklin