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.

A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis.

Delineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across psychotic disorders and may particularly be associated with negative symptoms, i.e. affective flattening, alogia and avolition. We have previously published evidence of association with a dysbindin risk haplotype derived from alleles C-A-T at SNPs P1655 (rs2619539), P1635 (rs3213207) and SNP66961 (rs2619538) in two independent schizophrenia (SZ) case-control samples. The C-A-T haplotype impacts at the level of gene function and phenotype: the haplotype indexes lower cortical expression of the dysbindin gene in post-mortem SZ brain samples and haplotype carriers show greater deficits in spatial working memory and early visual processing than non-carrier SZ patients. The aim of this study was to establish if the C-A-T dysbindin risk haplotype is associated with a specific clinical symptom profile. We investigated the relationship between the haplotype and PANSS-derived symptom factors in 262 individuals with schizophrenia/schizoaffective disorder using principal components analysis (PCA) and analysis of variance (ANOVA). Dysbindin risk carriers scored significantly less than non-carriers on the 'hostility/excitability' factor (F 1,196=8.468; p=.004), with a trend for higher negative symptom scores. This suggests that risk variation at the dysbindin gene may contribute to a more prototypical SZ presentation with less severe excitement/manic symptoms and more negative symptoms.

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.

D-amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia.

A series of genetic studies have identified the D-amino acid oxidase (DAO) gene as potentially contributing to schizophrenia susceptibility. An interacting gene, D-amino acid oxidase activator (DAOA) has also been implicated and it has been suggested that variation at these genes may influence the efficiency of glutamate gating at N-methyl-D-aspartate-type (NMDA) receptors. However, recent data suggests that DAOA may influence susceptibility to mood episodes across the spectrum of psychotic disorders rather than contributing to a specific psychosis phenotype. The aim of this study was to determine whether risk variation at DAO is similarly associated with affective or other clinical symptoms in psychosis. We have previously reported association between risk variation at DAO and schizophrenia in an Irish case-control sample. In this study we investigated the relationship between a defined genetic risk variant at DAO and PANSS-derived clinical symptom factors in a sample of 249 patients using principal component and Kruskal-Wallis analyses. Carriers of the DAO risk variant scored significantly higher on the 'depression/anxiety' factor than non-carriers (H=9.02, d.f.=2, p=0.01). These data suggest a potential role for DAO in susceptibility to depressive symptoms in schizophrenia, but a more general role for DAO in affective disorders cannot be excluded.

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.

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.

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.