Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137, Neuroscience Letters (2010Letters ( ), doi:10.1016Letters ( /j.neulet.2012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 17A c c e p t e d M a n u s c r i p t  We investigated the clinical symptom profiles of carriers of the schizophrenia mir137 risk allele. The sample included 821 patients with schizophrenia, schizoaffective disorder and bipolar I disorder. Risk allele carriers had lower scores for positive symptoms and less psychosis incongruity.  On neurocognitive testing in a subset, there were more cognitive deficits in risk allele carriers *Highlights (for review)

Mental state decoding difficulties are significant in BD. An important direction for further research will be to establish to what extent these deficits affect social and occupational functioning as a potential target for therapeutic intervention.

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P = 6.32 × 10−5, odds ratio (OR) = 1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10−6). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.