Search

The micro RNA 137 (miR-137) variant rs1625579 has been identified as a genome-wide significant risk variant for schizophrenia. miR-137 has an established role in neurodevelopment and may mediate cognitive dysfunction in schizophrenia. This role of miR-137 may be related to changes in brain morphology for risk-related genotypes; however this has not yet been delineated. Here we considered whether rs1625579 genotype was predictive of indices of brain structure in patients with schizophrenia and healthy controls. Structural magnetic resonance imaging (sMRI) data (i.e. 3T T1-TFE or 1.5T T1-MPRAGE) were acquired from 150 healthy controls and 163 schizophrenic patients. Two volumetric analyses that considered the impact of miR-137/rs1625579 genotype were carried out on sMRI data. In the first analysis, voxel based morphometry was employed to consider genotype-related variability in local grey and white matter across the entire brain volume. Our secondary analysis utilized the FIRST protocol in FSL to consider the volume of subcortical structures (i.e. bilateral accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus). Several brain regions in both analyses demonstrated the expected main effect of participant group (i.e. schizophrenics < controls), yet there were no regions where we observed an impact of rs1635579 genotype on brain volume. Our analyses suggest that the mechanism by which miR-137 confers risk for schizophrenia and impacts upon cognitive function may not be mediated by changes in local brain volume. However, it remains to be determined whether or not alternative measures of brain structure are related to these functions of miR-137., (© 2014 Wiley Periodicals, Inc.)

A single nucleotide polymorphism (SNP rs1625579) within the micro-RNA 137 (MIR137) gene recently achieved strong genome-wide association with schizophrenia (SZ). However, the mechanisms by which SZ risk may be mediated by this variant are unknown. As miRNAs have the potential to influence oligodendrocyte development, we investigated whether this SNP was associated with variability in white matter (WM) microstructure. Diffusion tensor imaging (DTI) was conducted on 123 healthy participants genotyped for rs1625579. The analysis consisted of whole-brain tract-based spatial statistics and atlas-based tractography analysis of six major WM tracts known to be affected in SZ - the inferior longitudinal fasciculus, the uncinate fasciculus, the inferior fronto-occipital fasciculus, the anterior thalamic radiation, the cingulum bundle and the corpus callosum. No significant differences in either whole-brain fractional anisotropy or mean diffusivity between MIR137 genotype groups were observed (p>0.05). Similarly, atlas-based tractography of particular tracts implicated in SZ failed to reveal any significant differences between MIR137 genotype groups on measures of WM connectivity (p>0.05). In the absence of WM effects comparable to those reported for other SZ associated genes, these data suggest that MIR137 alone may not confer variability in these WM measures and therefore may not act in isolation for any effects that the variant may have on WM microstructure in SZ samples., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity., (© The Author 2014. Published by Oxford University Press.)

Background: A single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown., Aims: To determine the impact of the rs7914558 risk 'G' allele [corrected] on measures of neurocognition, social cognition and brain structure., Method: Patients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39)., Results: No effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples., Conclusions: Although the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk., (Copyright © 2013 Wiley Periodicals, Inc.)

A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of the endophenotypic consequences of this variant, and our own investigations have suggested that the effects of this gene are not apparent at the level of cognitive function in patients or controls. Because the impact of risk variants may be more apparent at the level of brain, the aim of this investigation was to delineate whether NRGN genotype predicted variability in brain structure and/or function. Healthy individuals participated in structural (N = 140) and/or functional (N = 36) magnetic resonance imaging (s/fMRI). Voxel-based morphometry was used to compare gray and white matter volumes between carriers of the non-risk C allele (i.e., CC/CT) and those who were homozygous for the risk T allele. Functional imaging data were acquired during the performance of a spatial working memory task, and were also analyzed with respect to the difference between C carriers and T homozygotes. There was no effect of the NRGN variant rs12807809 on behavioral performance or brain structure. However, there was a main effect of genotype on brain activity during performance of the working memory task, such that while C carriers exhibited a load-independent decrease in left superior frontal gyrus/BA10, TT individuals failed to show a similar decrease in activity. The failure to disengage this ventromedial prefrontal region, despite preserved performance, may be indicative of a reduction in processing efficiency in healthy TT carriers. Although it remains to be established whether this holds true in larger samples and in patient cohorts, if valid, this suggests a potential mechanism by which NRGN variability might contribute to schizophrenia risk.

Background: The nitric oxide synthasase-1 gene ( NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear. Methods: We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task. Results: We found that carriers of the previously identified risk 'G' allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for. Conclusion: The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The hexonucleotide repeat expansion ‘GGGGCC’ at the C9ORF72 gene has been strongly linked with amyotrophic lateral sclerosis and frontotemporal dementia. There is some evidence for clinical and genetic overlap between frontotemporal dementia and schizophrenia. Here, we genotyped the repeat at C9ORF72 in a large Irish psychosis case-control sample (n = 2477). We found no carriers of >30 repeats. We found 7 samples with >22 repeats, 2 schizophrenia cases and 5 controls, but overall we observed no difference in the distribution of the repeat between our case and control samples. By using genome-wide association data to phase haplotypes at this gene, we investigated if carriers of the repeat expansion arose from a single common founder. All samples that carry 17 or more repeats also carry the founder haplotype and overall there is a very strong correlation between repeat length and the founder haplotype (Spearman rho = 0.714, p < 0.001). Our study provides further evidence to bolster the claim that carriers of the repeat expansion at C9ORF72 arose from a single common founder. [Copyright &y& Elsevier]

Abstract: Background: MIR137 is implicated in brain development and encodes a microRNA that regulates neuronal maturation and adult neurogenesis. Recently, a common genetic variant within MIR137 showed genome wide evidence of association with schizophrenia, and with altered amygdala activation in those at genetic risk for schizophrenia. Following this evidence, we investigated the effects of MIR137 genotype on neuronal activity during face processing. Methods: By grouping 81 healthy participants as carrier or non-carriers of the MIR137 rs1625579 risk allele associated with schizophrenia, we investigated MIR137's effects on altered cortical response during an fMRI face processing task and altered functional connectivity using the amygdala as a seed region. Results: Homozygous carriers of the risk allele were observed to show relatively increased functional connectivity between the right amygdala and frontal regions that play a key role in emotion processing and regulation (e.g. the cingulate and prefrontal cortex). Conclusions: Our findings provide the first evidence that the rs1625579 variant affects fronto-amygdala functional connectivity, providing further evidence that MIR137 may contribute to forms of psychosis in which affective symptoms are more prominent. [Copyright &y& Elsevier]

Abstract: A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N=157), voxel based morphometry was used to compare grey matter (GM) volume between homozygous and heterozygous carriers of the ‘G’ allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk ‘A’ allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in ‘G’ allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency, which may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function. [Copyright &y& Elsevier]