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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.

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.

We undertook an RNA sequencing (RNAseq)-based transcriptomic profiling study on lymphoblastoid cell lines of a European ancestry sample of 529 schizophrenia cases and 660 controls, and found 1058 genes to be differentially expressed by affection status. These differentially expressed genes were enriched for involvement in immunity, especially the 697 genes with higher expression in cases. Comparing the current RNAseq transcriptomic profiling to our previous findings in an array-based study of 268 schizophrenia cases and 446 controls showed a highly significant positive correlation over all genes. Fifteen (18%) of the 84 genes with significant (false discovery rate<0.05) expression differences between cases and controls in the previous study and analyzed here again were differentially expressed by affection status here at a genome-wide significance level (Bonferroni P<0.05 adjusted for 8141 analyzed genes in total, or P<~6.1 × 10 -6 ), all with the same direction of effect, thus providing corroborative evidence despite each sample of fully independent subjects being studied by different technological approaches. Meta-analysis of the RNAseq and array data sets (797 cases and 1106 controls) showed 169 additional genes (besides those found in the primary RNAseq-based analysis) to be differentially expressed, and provided further evidence of immune gene enrichment. In addition to strengthening our previous array-based gene expression differences in schizophrenia cases versus controls and providing transcriptomic support for some genes implicated by other approaches for schizophrenia, our study detected new genes differentially expressed in schizophrenia. We highlight RNAseq-based differential expression of various genes involved in neurodevelopment and/or neuronal function, and discuss caveats of the approach.

We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Identifying genes that contribute to white matter microstructure should provide insights into the neurobiological processes that regulate white matter development, plasticity and pathology. We detected five significant SNPs using genome-wide association analysis on a global measure of fractional anisotropy in 776 individuals from large extended pedigrees. Genetic correlations and genome-wide association results indicated that the genetic signal was largely homogeneous across white matter regions. Using RNA transcripts derived from lymphocytes in the same individuals, we identified two genes (GNA13 and CCDC91) that are likely to be cis-regulated by top SNPs, and whose expression levels were also genetically correlated with fractional anisotropy. A transcript of HTR7 was phenotypically associated with FA, and was associated with an intronic genome-wide significant SNP. These results encourage further research in the mechanisms by which GNA13, HTR7 and CCDC91 influence brain structure, and emphasize a role for g-protein signaling in the development and maintenance of white matter microstructure in health and disease., (Published by Elsevier Inc.)

Schizophrenia genome-wide association studies (GWAS) have identified common SNPs, rare copy number variants (CNVs) and a large polygenic contribution to illness risk, but biological mechanisms remain unclear. Bioinformatic analyses of significantly associated genetic variants point to a large role for regulatory variants. To identify gene expression abnormalities in schizophrenia, we generated whole-genome gene expression profiles using microarrays on lymphoblastoid cell lines (LCLs) from 413 cases and 446 controls. Regression analysis identified 95 transcripts differentially expressed by affection status at a genome-wide false discovery rate (FDR) of 0.05, while simultaneously controlling for confounding effects. These transcripts represented 89 genes with functions such as neurotransmission, gene regulation, cell cycle progression, differentiation, apoptosis, microRNA (miRNA) processing and immunity. This functional diversity is consistent with schizophrenia's likely significant pathophysiological heterogeneity. The overall enrichment of immune-related genes among those differentially expressed by affection status is consistent with hypothesized immune contributions to schizophrenia risk. The observed differential expression of extended major histocompatibility complex (xMHC) region histones (HIST1H2BD, HIST1H2BC, HIST1H2BH, HIST1H2BG and HIST1H4K) converges with the genetic evidence from GWAS, which find the xMHC to be the most significant susceptibility locus. Among the differentially expressed immune-related genes, B3GNT2 is implicated in autoimmune disorders previously tied to schizophrenia risk (rheumatoid arthritis and Graves' disease), and DICER1 is pivotal in miRNA processing potentially linking to miRNA alterations in schizophrenia (e.g. MIR137, the second strongest GWAS finding). Our analysis provides novel candidate genes for further study to assess their potential contribution to schizophrenia.

Methods of multiple comparisons were applied to linkage analysis in the case of genome scanning. Data for Problem 2A were used. p-Values were calculated for all 440,400 possible tests of linkage. Plots of distribution functions and false discovery rate are shown.

A genetic and epidemiological sample of 20-59-year-old males, Moscow residents (n = 3141), was surveyed. The authors obtained data on the prevalence of coronary heart disease from epidemiological criteria and genealogical data on cardiovascular diseases by the "Familial History" questionnaire in the first-degree relatives who were interviewed by using a genetic and mathematical monolocus diallelic model. It was found that out of the 10 possible variants under study a genetic and environmental variant with independent penetrance of 3 genotypes adequately describes the prevalence of coronary heart disease in the families and in the population. This suggest that both genetic and environmental factors have an influence on the prevalence of coronary heart disease and that there is a possible genetic polymorphism of the disease.

The ascertainment of probands according to place of residence in hospitals or in the community has enabled our sampling to be representative of whole subpopulations of patients. Probands from psychiatric hospitals are characterized by biased clinical parameters. Our sampling procedure provides important preliminary results which appear to be contradictory to those produced by conventional sampling methods.

Analysis of the character of the linear relation between the totality and some factors (the number of beds, psychiatrists working at hospitals and on an outpatient basis) that characterize the psychiatric services in 18 regions of Siberia and the Far East over 16 years as well as between the identification of new cases of schizophrenia, epilepsy, alcoholism, neuroses, psychoses and oligophrenia has demonstrated a high efficacy of the totality of factors. The differences have been shown between the regions in respect to the relation of the factors to the disease incidence, explained by the authors by the specificity of the organizational structure of the psychiatric services and by a number of other factors.

The method of estimation of parameters of monolocus diallele model (MDM) of qualitative trait on relative group data is described, these parameters being the number of affected and normal proband relatives of the arbitrary family degree and siblings in different matings types. For the case of single ascertainment, the expressions of corresponding probabilities have been taken as functions of MDM parameters using ITO matrixes and genetic transition matrix. Estimation of parameters was obtained by the maximum likelyhood method. Hardy-Weinberg equilibrium is not always necessary for this method; some weak requirement of stationarity is quite enough.

The article deals with the assessment of the main components and canonic correlations reflecting the relationship between the resources of psychiatric care (a number of beds and psychiatrists providing medical care in hospitals and in other settings) and the rate of identification and incidence of psychoses, schizophrenia, epilepsy, alcoholism, neuroses and oligophrenia in Siberia and Far East over a period of 16 years (from 1965 to 1981 excluding 1978). The first main component covered up to 80.1% of the dispersion range of the identification rate and 94.5% of the incidence rate, the second component covered up to 37.1% and 21% respectively. Canonic correlations proved higher for the incidence rate as against the identification rate. Although there were substantial differences in the studied interrelationship with regard to a number of territories, the main tendency was expressed in a marked linear correlation between a growth in the resources of psychiatric service and the time-course of the rates of the studied pathology.

Based on ITO matrices, a method for parameter estimation of the monolocus diallele model (MDM) of qualitative trait is described, taking account of non-genetic (environmental) factors. The model parameters, probabilities of relatives' affection, constructing the likelihood function and testing hypotheses of the effect of environmental factors on the penetrations of MDM genotypes are outlined. Examples are given, concerning estimation of epilepsy MDM parameters, taking account of two factors-harmfulness of antenatal ontogenesis period and harmfulness which provokes paroxysms.

The initial data for the analysis have resulted in epidemiologic (547 patients) and genetic-epidemiologic (365 patients) study of patients with diagnosis of epilepsy living in five districts of the Khabarovsk Territory. The population frequency of epilepsy was equal to 0.288%. With the use of data on numbers of sick and healthy first-third-degree relatives, and the method of maximum likelihood, the monolocus diallelic model (MDM) parameters of the family and population epilepsy prevalence were estimated. For each of 9 MDM variants two decisions were obtained, depending on the use of population probability of the feature. The analysis of 8 sets of initial data allowed to ascertain the influence of information about the first-third-degree relatives on parameter estimates. The calculation results are presented for one of initial data sets (set A). Three MDM variants were shown to predict the values of the relative affection probability, these being rather close to frequencies observed. The arguments are presented in favour of quasi-dominant variant with following parameters: frequency of mutant allele in a population - 5.28%, homozygote penetrance - 21.5% and that for heterozygote - 2.6%. According to parameter estimates within this model, the probability of offspring disease in the family with the known number of sick and healthy parents was calculated.

The authors have demonstrated the existence of linear correlation between the complex of three factors (the number of beds and psychiatrists in hospitals and outpatient clinics) and incidence rate (over a period of 16 years) of neuroses in 11 administrative areas, epilepsy, in 12 areas, psychoses, in 15, oligophrenia, in 17, alcoholism and schizophrenia in all 18 areas of Siberia and the Far East. Correlations of each of the three factors with the morbidity rate varied within a wide range in relation to both administrative areas and individual diseases. The authors draw attention to the importance of supplementing the growth of resources of psychiatric service with new forms and methods of work.