Association between schizophrenia polygenic risk and neural correlates of emotion perception.

The neural correlates of emotion perception have been shown to be significantly altered in schizophrenia (SCZ) patients as well as their healthy relatives, possibly reflecting genetic susceptibility to the disease. The aim of the study was to investigate the association between SCZ polygenic risk and brain activity whilst testing perception of multisensory, dynamic emotional stimuli. We created SCZ polygenic risk scores (PRS) for a sample of twenty-eight healthy individuals. The PRS was based on data from the Psychiatric Genomics Consortium and was used as a regressor score in the neuroimaging analysis. The results of a multivariate brain-behaviour analysis show that higher SCZ PRS are related to increased activity in brain regions critical for emotion during the perception of threatening (angry) emotions. These results suggest that individuals with higher SCZ PRS over-activate the neural correlates underlying emotion during perception of threat, perhaps due to an increased experience of fear or neural inefficiency in emotion-regulation areas. Moreover, over-recruitment of emotion regulation regions might function as a compensation to maintain normal emotion regulation during threat perception. If replicated in larger studies, these findings may have important implications for understanding the neurophysiological biomarkers relevant in SCZ

MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10−5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects

Analysis of A-to-I RNA Editing in Schizophrenia Risk Gene MIR137

Schizophrenia is a complex psychiatric disorder that likely emerges as a result of interacting genetic and environmental risk factors. A prominent hypothesis for the etiology of schizophrenia is that schizophrenia emerges as a result of pre- and/or perinatal viral infection-induced inflammation in genetically predisposed individuals. This gene-environment interaction may be mediated by genetic regulators such as microRNA 137 (miR137), a regulatory RNA with a set of related SNPs that is highly associated with schizophrenia, and epigenetic phenomena such as RNA editing, which has been previously associated with schizophrenia and infection. Here I interrogate this gene-environment interaction by quantifying RNA editing of miR137, assessing the functional impact of this editing, and predicting its effects on schizophrenia risk in conjunction with a risk SNP. High-throughput RNA sequencing coupled to the PrimerID methodology revealed that miR137 is edited at a statistically significant level (p < 0.05) in both fetal human brain and adult mouse brain. Site-directed mutagenesis and luciferase assays demonstrated that A-to-I modification of certain pertinent bases in miR137 impart a large decrease in affinity to a target sequence. Finally, mathematical modeling and simulations based on empirical findings suggest that this RNA editing and a MIR137 schizophrenia-risk SNP significantly modulate inflammation-based schizophrenia risk burden (p < 2 x 10-16). These findings demonstrate that infection, the MIR137 gene, and RNA editing likely interact to promote schizophrenia risk, and thus this study serves to elucidate the cooperative influences of genetic and environmental risk factors on schizophrenia.Bachelor of Science in Public Healt

Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R2 = 0.008, Beta = −0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure

Does imaging genetics reveal shared mechanisms behind psychotic symptom profile?

Current diagnoses of schizophrenia (SZ) and bipolar disorder (BD) are classified by phenomenological principles and clinical descriptions. The boundaries of the disorders are merging with accumulating shared genetic and brain mechanisms being uncovered. Imaging genetics is a useful tool to understand the impact of genetic variations on the brain. It also enables capturing the behavioral implication of those genes and associated brain alterations. This study aimed to reveal the associations among sets of genetic variations, structural brain abnormalities, and clinical symptom profiles shared in schizophrenia and bipolar disorders by imaging genetics and multivariate approaches. First, we mapped the symptom profiles onto brain patterns. Distinct structural brain patterns guided with symptom profiles represented by positive and negative syndrome scale (PANSS), through parallel independent component analysis (pICA) were extracted. Brain patterns related to positive symptoms, mood, and apathy were discovered in SZ and BD. Second, we investigated the relationships of symptoms and brain patterns regardless of diagnostic categories by projecting each disorder’s structural brain and PANSS patterns into the other disorder group (e.g., projecting patterns from schizophrenia to bipolar and vice versa) to reassess the associations. The projected brain patterns showed associations with broad symptoms rather than the original PANSS patterns. Finally, we explored the potential shared genetic mechanisms behind symptom-brain patterns by investigating the effect of polygenic risk scores (PRS) from the Psychiatric Genomics Consortium (PGC). Both SZ and BD PRS were significantly associated with the positive symptom-related brain patterns in SZ. Higher genetic risks contributed to more severe gray matter concentration (GMC) reductions in the temporal regions of SZ patients, and it may lead to worse positive symptoms. Correspondingly, in the BD, both SZ and BD PRS were significantly associated with the mood symptom-related brain patterns. Higher risks contributed to more severe gray matter concentration (GMC) reductions in the frontal-temporal-parietal circuits with worse mood symptoms. The polygenic effects behind the apathy component may be subtle. The results helped improve the understanding of categories of psychotic disorders starting from schizophrenia and bipolar disorder. It may essentially contribute to the more precise diagnosis and treatment for heterogeneous populations with psychosis

The role of miR-137 in schizophrenia

The genetic basis of schizophrenia is still largely unknown. Recent evidence suggests that a microRNA (miRNA), miR-137 may be involved. The first large schizophrenia genome wide association (GWAS) study, published in 2011, identified a variant within the host gene of this miRNA (MIR-137) as the top association. Since then, further evidence for the potential influence of this miRNA within the disorder has accumulated. These studies used a variety of methods from GWAS to neuroimaging. However, few studies have evaluated the mechanism for the association of the MIR-137 variant, nor how alterations in the miRNA may have downstream effects on its targets and the function of these targets within biological pathways. We hypothesized that the target genes of miR-137 are involved in schizophrenia relevant pathways, such as those affecting neuronal development and plasticity, and that the MIR-137 risk-associated variant may lead to altered regulation of such pathways. We predict that variants within the targets of the miRNA may further alter target regulation. Here we completed the following three aims to determine the potential impact of dysregulation by this miRNA in schizophrenia. 1) We characterized the targets of the miRNA and the pathways over-representing these genes. 2) We determined the schizophrenia-risk association of these targets within these target enriched pathways. 3) We evaluated the influence of variants within target genes of an enriched pathway and the previously associated miR-137 host gene variant on structural gray matter. Our results suggest that the targets of this miRNA are indeed involved in pathways relevant to neuronal development and plasticity and thus the development of schizophrenia. The target genes within these pathways contain variants associated with schizophrenia that may disrupt regulation by the miRNA. Variants within targets of the PKA signaling pathway coupled with the MIR-137 variant may influence the development of gray matter within the occipital, temporal, and parietal lobe. Overall, our studies further suggest that this miRNA is influential in schizophrenia and provide a map for future studies to determine the effects of dysregulation by miR-137 in the disorder

microRNAs Sculpt Neuronal Communication in a Tight Balance That Is Lost in Neurological Disease

Since the discovery of the first microRNA 25 years ago, microRNAs (miRNAs) have emerged as critical regulators of gene expression within the mammalian brain. miRNAs are small non-coding RNAs that direct the RNA induced silencing complex to complementary sites on mRNA targets, leading to translational repression and/or mRNA degradation. Within the brain, intra- and extracellular signaling events tune the levels and activities of miRNAs to suit the needs of individual neurons under changing cellular contexts. Conversely, miRNAs shape neuronal communication by regulating the synthesis of proteins that mediate synaptic transmission and other forms of neuronal signaling. Several miRNAs have been shown to be critical for brain function regulating, for example, enduring forms of synaptic plasticity and dendritic morphology. Deficits in miRNA biogenesis have been linked to neurological deficits in humans, and widespread changes in miRNA levels occur in epilepsy, traumatic brain injury, and in response to less dramatic brain insults in rodent models. Manipulation of certain miRNAs can also alter the representation and progression of some of these disorders in rodent models. Recently, microdeletions encompassing MIR137HG, the host gene which encodes the miRNA miR-137, have been linked to autism and intellectual disability, and genome wide association studies have linked this locus to schizophrenia. Recent studies have demonstrated that miR-137 regulates several forms of synaptic plasticity as well as signaling cascades thought to be aberrant in schizophrenia. Together, these studies suggest a mechanism by which miRNA dysregulation might contribute to psychiatric disease and highlight the power of miRNAs to influence the human brain by sculpting communication between neurons

Controlo Postural e Mobilidade Funcional em Tarefa Simples e Dupla na Esquizofrenia

O estudo das alterações motoras não é recente, mas a sua concetualização como característica intrínseca da esquizofrenia não está clara. Por seu lado, patente está a inter-relação entre competências cognitivas e motoras, daí a pertinência de estudar o comportamento motor em tarefa simples e dupla. Objetivo: Analisar o controlo postural e a mobilidade funcional em tarefa simples e dupla de pessoas com diagnóstico de esquizofrenia, comparativamente a um grupo controlo. Métodos: Utilizaram-se a plataforma de forças para avaliar o Sit-to-Stand e o equilíbrio estático; o Timed Up and Go para avaliar a mobilidade funcional; e o programa Kinovea para analisar a orientação e estabilidade posturais durante o movimento de Sit-to-Stand-to-Sit. Recorreu-se ao teste t-Student e de Mann-Whitney, tal como à ANOVA para medidas repetidas com modelo misto. Resultados: Participaram 27 indivíduos, 13 com diagnóstico de esquizofrenia e 14 sem diagnóstico. Não se encontrou correlação entre as variáveis clínicas e os domínios avaliados, tal como não houve diferenças significativas no desempenho cognitivo por grupos. Porém, o desempenho motor mostrou discrepâncias estatísticas entre grupos para alguns dos testes aplicados. Conclusão: Esta investigação parece sugerir a existência de alterações motoras associada à esquizofrenia, principalmente quando em tarefa dupla. Ainda assim, mais estudos são necessários.The study of motor disorders is not recent, but its conceptualization as an intrinsic characteristic of schizophrenia is unclear. On the other hand, the interrelationship between cognitive and motor skills is evident, hence the relevance of studying motor behavior in simple and dual task. Objective: To analyze postural control and functional mobility in simple and dual task of people diagnosed with schizophrenia, compared to a control group. Methods: The force platform was used to evaluate the Sit-to-Stand and the static balance; the Timed Up and Go to evaluate functional mobility; and the Kinovea program to analyze postural orientation and stability during the Sit-to-Stand-to-Sit movement. The t-Student and Mann-Whitney test was used, as well as the ANOVA for repeated measures with a mixed model. Results: 27 individuals participated, 13 with diagnosis of schizophrenia and 14 without diagnosis. No correlation was found between the clinical variables and the evaluated domains, just as there were no significant differences in cognitive performance by groups. However, motor performance showed statistical discrepancies between groups for some of the applied tests. Conclusion: This research seems to suggest the existence of motor changes associated with schizophrenia, mainly when in a dual task. Still, more studies are needed