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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]

Abstract: ZNF804A rs1344706 is the first genetic risk variant to achieve genome wide significance for psychosis. Following earlier evidence that patients carrying the ZNF804A risk allele had relatively spared memory function compared to patient non-carriers, we investigated whether ZNF804A was also associated with variation in brain volume. In a sample of 70 patients and 38 healthy participants we used voxel based morphometry to compare homozygous (AA) carriers of the ZNF804A risk allele to heterozygous and homozygous (AC/CC) non-carriers for both whole brain volume and specific regions implicated in earlier ZNF804A studies—the dorsolateral pre-frontal cortex, the hippocampus, and the amygdala. For patients, but not for controls, we found that homozygous ‘AA’ risk carriers had relatively larger gray matter volumes than heterozygous/homozygous non-carriers (AC/CC), particularly for hippocampal volumes. These data are consistent with our earlier behavioral data and suggest that ZNF804A is delineating a schizophrenia subtype characterized by relatively intact brain volume. Establishing if this represents a discrete molecular pathogenesis with consequences for nosology and treatment will be an important next step in understanding ZNF084A''s role in illness risk. [Copyright &y& Elsevier]