Evidence of an interaction between FXR1 and GSK3β polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

Introduction: Genome Wide Association Studies (GWAS) have identified several genes associated with schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. Additionally, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, FXR1 (Fragile-X mental-retardation-syndrome-related 1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by Glycogen Synthase Kinase-3 (GSK3), which has been implicated in pathophysiology of SCZ and response to Antipsychotics (APs). rs496250 and rs12630592, two eQTLs of FXR1 and GSK3 respectively, interact on emotion stability and amygdala/PFC activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NS) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods: To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and fxr1 expression, as already reported for GSK3 expression. Results: We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion: Our findings suggest that, like GSK3 , FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3 pathway for NS of SCZ

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia

Tumori stromali gastrici:su tre casi clinici trattati con resezioni videoassistite

In conclusione riteniamo che: 1) i GIST debbano essere trattati con ampia terapia resettiva in quanto la loro potenziale malignità è imprevedibile utilizzando i tradizionali parametri prognostici; 2) la loro exeresi è notevolmente semplificata dall’ausilio della assistenza videolaparoscopica. 3) lo studio istopatologico definitivo è cruciale per la verifica della adeguatezza della exeresi e per la definizine del successivo follow-up dei pazient

A polygenic score indexing a DRD2-related co-expression network is associated with striatal dopamine function

The D2 dopamine receptor (D2R) is the primary site of the therapeutic action of antipsychotics and is involved in essential brain functions relevant to schizophrenia, such as attention, memory, motivation, and emotion processing. Moreover, the gene coding for D2R (DRD2) has been associated with schizophrenia at a genome-wide level. Recent studies have shown that a polygenic co-expression index (PCI) predicting the brain-specific expression of a network of genes co-expressed with DRD2 was associated with response to antipsychotics, brain function during working memory in patients with schizophrenia, and with the modulation of prefrontal cortex activity after pharmacological stimulation of D2 receptors. We aimed to investigate the relationship between the DRD2 gene network and in vivo striatal dopaminergic function, which is a phenotype robustly associated with psychosis and schizophrenia. To this aim, a sample of 92 healthy subjects underwent 18F-DOPA PET and was genotyped for genetic variations indexing the co-expression of the DRD2-related genetic network in order to calculate the PCI for each subject. The PCI was significantly associated with whole striatal dopamine synthesis capacity (p = 0.038). Exploratory analyses on the striatal subdivisions revealed a numerically larger effect size of the PCI on dopamine function for the associative striatum, although this was not significantly different than effects in other sub-divisions. These results are in line with a possible relationship between the DRD2-related co-expression network and schizophrenia and extend it by identifying a potential mechanism involving the regulation of dopamine synthesis. Future studies are needed to clarify the molecular mechanisms implicated in this relationship

Consensus molecular environment of schizophrenia risk genes in coexpression networks shifting across age and brain regions

Schizophrenia is a neurodevelopmental brain disorder whose genetic risk is associated with shifting clinical phenomena across the life span. We investigated the convergence of putative schizophrenia risk genes in brain coexpression networks in postmortem human prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and dentate gyrus granule cells, parsed by specific age periods (total N = 833). The results support an early prefrontal involvement in the biology underlying schizophrenia and reveal a dynamic interplay of regions in which age parsing explains more variance in schizophrenia risk compared to lumping all age periods together. Across multiple data sources and publications, we identify 28 genes that are the most consistently found partners in modules enriched for schizophrenia risk genes in DLPFC; twenty-three are previously unidentified associations with schizophrenia. In iPSC-derived neurons, the relationship of these genes with schizophrenia risk genes is maintained. The genetic architecture of schizophrenia is embedded in shifting coexpression patterns across brain regions and time, potentially underwriting its shifting clinical presentation