Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10-5; ΔAIC = -10.5) and is highly enriched for genes related to ribosomal proteins and translation (FDR = 4 × 10-141), mitochondrial oxidative phosphorylation, and neurodegeneration. SNP association testing revealed tentative QTLs underlying module co-expression, notably at FASTKD2 (top P = 2.8 × 10-6), a gene involved in mitochondrial translation. These results substantiate the role of translational machinery in SZ pathogenesis, providing insights into a possible dopaminergic mechanism disrupting mitochondrial function, and demonstrates the utility of disease-relevant functional perturbation in the study of complex genetic etiologies

Essential spectra of difference operators on \sZ^n-periodic graphs

Let (\cX, \rho) be a discrete metric space. We suppose that the group \sZ^n acts freely on $X$ and that the number of orbits of $X$ with respect to this action is finite. Then we call $X$ a \sZ^n-periodic discrete metric space. We examine the Fredholm property and essential spectra of band-dominated operators on $l^p(X)$ where $X$ is a \sZ^n-periodic discrete metric space. Our approach is based on the theory of band-dominated operators on \sZ^n and their limit operators. In case $X$ is the set of vertices of a combinatorial graph, the graph structure defines a Schr\"{o}dinger operator on $l^p(X)$ in a natural way. We illustrate our approach by determining the essential spectra of Schr\"{o}dinger operators with slowly oscillating potential both on zig-zag and on hexagonal graphs, the latter being related to nano-structures

Preliminary Sunyaev Zel'dovich Observations of Galaxy Clusters with OCRA-p

We present 30 GHz Sunyaev Zel'dovich (SZ) observations of a sample of four galaxy clusters with a prototype of the One Centimetre Receiver Array (OCRA-p) which is mounted on the Torun 32-m telescope. The clusters (Cl0016+16, MS0451.6-0305, MS1054.4-0321 and Abell 2218) are popular SZ targets and serve as commissioning observations. All four are detected with clear significance (4-6 sigma) and values for the central temperature decrements are in good agreement with measurements reported in the literature. We believe that systematic effects are successfully suppressed by our observing strategy. The relatively short integration times required to obtain these results demonstrate the power of OCRA-p and its successors for future SZ studies.Comment: 9 pages, 2 figures. Accepted by MNRAS, online earl

Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention

CO-MORBIDITY BETWEEN MAJOR DEPRESSION AND SCHIZOPHRENIA: PREVALENCE AND CLINICAL CHARACTERISTICS

Backround: The aim of this study was to explore the co-morbidity between Major Depressive Disorder (MDD) and Schizophrenia (SZ) among a large number of patients describing their clinical characteristics and rate of prevalence. Subjects and methods: A cohort-study was carried out on 396 patients affected by MDD and SZ who consecutively attended the Department of Psychiatry, Rumeilah Hospital in Qatar. We employed the World Health Organization - Composite International Diagnostic Interview (WHO CIDI) and the Structured Clinical Interview for DSM-5 (SCID-5) for diagnoses. Patients were also grouped in MDD patients with and without co-morbid SZ (MDD vs MDD/SZ) for comparisons. Results: A total of 396 subjects were interviewed. MDD patients with comorbid SZ (146(36.8%)) were 42.69±14.33 years old whereas MDD without SZ patients (250 (63.2%)) aged 41.59±13.59. Statistically significant differences between MDD with SZ patients and MDD without SZ patients were: higher BMI (Body Mass Index) (p=0.025), lower family income (p=0.004), higher rate of cigarette smoking (p<0.001), and higher level of consanguinity (p=0.023). Also, statistically significant differences were found in General Health Score (p=0.017), Clinical Global Impression-BD Score (p=0.042), duration of illnesses (p=0.003), and Global Assessment of Functioning (p=0.012). Rates of anxiety dimensions (e.g.: general anxiety, agoraphobia, somatisation, etc.), mood dimensions (e.g.: major depression, mania, oppositional defiant behaviour, Bipolar disorder), Attention Deficit Hyperactivity Disorder, psychotic and personality dimensions were higher among MDD with SZ patients than MDD without SZ. Conclusion: This study confirms that MDD with SZ is a common comorbidity especially among patients reporting higher level of consanguinity. MDD/SZ comorbidity presents unfavourable clinical characteristics and higher levels of morbidity at rating scales

Solute Carrier Family 1 (SLC1A1) Contributes to Susceptibility and Psychopathology Symptoms of Schizophrenia in the Han Chinese Population

Objective: Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamate hypothesis describes one possible pathogenesis of SZ. The solute carrier family 1 gene (SLC1A1) is one of several genes thought to play a critical role in regulating the glutamatergic system and is strongly implicated in the pathophysiology of SZ. In this study, we identify polymorphisms of the SLC1A1 gene that may confer susceptibility to SZ in the Han Chinese population. Methods: We genotyped 36 single-nucleotide polymorphisms (SNPs) using Illumina GoldenGate assays on a BeadStation 500G Genotyping System in 528 paranoid SZ patients and 528 healthy controls. Psychopathology was rated by the Positive and Negative Symptom Scale. Results: Significant associations were found in genotype and allele frequencies for SNPs rs10815017 (p = 0.002, 0.030, respectively) and rs2026828 (p = 0.020, 0.005, respectively) between SZ and healthy controls. There were significant associations in genotype frequency at rs6476875 (p = 0.020) and rs7024664 (p = 0.021) and allele frequency at rs3780412 (p = 0.026) and rs10974573 (p = 0.047) between SZ and healthy controls. Meanwhile, significant differences were found in genotype frequency at rs10815017 (p = 0.015), rs2026828 (p = 0.011), and rs3780411 (p = 0.040) in males, and rs7021569 in females (p = 0.020) between cases and controls when subdivided by gender. Also, significant differences were found in allele frequency at rs2026828 (p = 0.003), and rs7021569 (p = 0.045) in males, and rs10974619 in females (p = 0.044). However, those associations disappeared after Bonferroni\u27s correction (p\u27s \u3e 0.05). Significant associations were found in the frequencies of four haplotypes (AA, CA, AGA, and GG) between SZ and healthy controls (chi (2) = 3.974, 7.433, 4.699, 4.526, p = 0.046, 0.006, 0.030, 0.033, respectively). There were significant associations between rs7032326 genotypes and PANSS total, positive symptoms, negative symptoms, and general psychopathology in SZ (p = 0.002, 0.011, 0.028, 0.008, respectively). Conclusion: The present study provides further evidence that SLC1A1 may be not a susceptibility gene for SZ. However, the genetic variations of SLC1A1 may affect psychopathology symptoms