Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia

Accounting students' IT applicaton skills over a 10-year period

This paper reports on the changing nature of a range of information technology (IT) application skills that students declare on entering an accounting degree over the period from 1996 to 2006. Accounting educators need to be aware of the IT skills students bring with them to university because of the implications this has for learning and teaching within the discipline and the importance of both general and specific IT skills within the practice and craft of accounting. Additionally, IT skills constitute a significant element within the portfolio of employability skills that are increasingly demanded by employers and emphasized within the overall Higher Education (HE) agenda. The analysis of students' reported IT application skills on entry to university, across a range of the most relevant areas of IT use in accounting, suggest that their skills have continued to improve over time. However, there are significant differential patterns of change through the years and within cohorts. The paper addresses the generalizability of these findings and discusses the implications of these factors for accounting educators, including the importance of recognising the differences that are potentially masked by the general increase in skills; the need for further research into the changing nature, and implications, of the gender gap in entrants' IT application skills; and the low levels of entrants' spreadsheet and database skills that are a cause for concern

Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Targeted Inhibition of miRNA Maturation with Morpholinos Reveals a Role for miR-375 in Pancreatic Islet Development

Several vertebrate microRNAs (miRNAs) have been implicated in cellular processes such as muscle differentiation, synapse function, and insulin secretion. In addition, analysis of Dicer null mutants has shown that miRNAs play a role in tissue morphogenesis. Nonetheless, only a few loss-of-function phenotypes for individual miRNAs have been described to date. Here, we introduce a quick and versatile method to interfere with miRNA function during zebrafish embryonic development. Morpholino oligonucleotides targeting the mature miRNA or the miRNA precursor specifically and temporally knock down miRNAs. Morpholinos can block processing of the primary miRNA (pri-miRNA) or the pre-miRNA, and they can inhibit the activity of the mature miRNA. We used this strategy to knock down 13 miRNAs conserved between zebrafish and mammals. For most miRNAs, this does not result in visible defects, but knockdown of miR-375 causes defects in the morphology of the pancreatic islet. Although the islet is still intact at 24 hours postfertilization, in later stages the islet cells become scattered. This phenotype can be recapitulated by independent control morpholinos targeting other sequences in the miR-375 precursor, excluding off-target effects as cause of the phenotype. The aberrant formation of the endocrine pancreas, caused by miR-375 knockdown, is one of the first loss-of-function phenotypes for an individual miRNA in vertebrate development. The miRNA knockdown strategy presented here will be widely used to unravel miRNA function in zebrafish

Autism genetic database (AGD): a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites

<p>Abstract</p> <p>Background</p> <p>Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In the present work, the Autism Genetic Database (AGD) was developed as a literature-driven, web-based, and easy to access database designed with the aim of creating a comprehensive repository for all the currently reported genes and genomic copy number variations (CNVs) associated with autism in order to further facilitate the assessment of these autism susceptibility genetic factors.</p> <p>Description</p> <p>AGD is a relational database that organizes data resulting from exhaustive literature searches for reported susceptibility genes and CNVs associated with autism. Furthermore, genomic information about human fragile sites and noncoding RNAs was also downloaded and parsed from miRBase, snoRNA-LBME-db, piRNABank, and the MIT/ICBP siRNA database. A web client genome browser enables viewing of the features while a web client query tool provides access to more specific information for the features. When applicable, links to external databases including GenBank, PubMed, miRBase, snoRNA-LBME-db, piRNABank, and the MIT siRNA database are provided.</p> <p>Conclusion</p> <p>AGD comprises a comprehensive list of susceptibility genes and copy number variations reported to-date in association with autism, as well as all known human noncoding RNA genes and fragile sites. Such a unique and inclusive autism genetic database will facilitate the evaluation of autism susceptibility factors in relation to known human noncoding RNAs and fragile sites, impacting on human diseases. As a result, this new autism database offers a valuable tool for the research community to evaluate genetic findings for this complex multifactorial disorder in an integrated format. AGD provides a genome browser and a web based query client for conveniently selecting features of interest. Access to AGD is freely available at <url>http://wren.bcf.ku.edu/</url>.</p

The relationship between job satisfaction, burnout, and turnover intention among physicians from urban state-owned medical institutions in Hubei, China: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Throughout China, a growing number of physicians are leaving or intending to depart from their organizations owing to job dissatisfaction. Little information is available about the role of occupational burnout in this association. We set out to analyze the relationship between job satisfaction, burnout, and turnover intention, and further to determine whether occupational burnout can serve as a mediator among Chinese physicians from urban state-owned medical institutions.</p> <p>Methods</p> <p>A cross-sectional survey was carried out in March 2010 in Hubei Province, central China. The questionnaires assessed sociodemographic characteristics, job satisfaction, burnout, and turnover intention. The job satisfaction and occupational burnout instruments were obtained by modifying the Chinese Physicians' Job Satisfaction Questionnaire (CPJSQ) and the Chinese Maslach Burnout Inventory (CMBI), respectively. Such statistical methods as one-way ANOVA, Pearson correlation, GLM-univariate and structural equation modeling were used.</p> <p>Results</p> <p>Of the 1600 physicians surveyed, 1451 provided valid responses. The respondents had medium scores (3.18 +/-0.73) on turnover intention, in which there was significant difference among the groups from three urban areas with different development levels. Turnover intention, which significantly and negatively related to all job-satisfaction subscales, positively related to each subscale of burnout syndrome. Work environment satisfaction (<it>b </it>= -0.074, <it>p < 0.01</it>), job rewards satisfaction (<it>b </it>= -0.073, <it>p < 0.01</it>), organizational management satisfaction (<it>b </it>= -0.146, <it>p < 0.01</it>), and emotional exhaustion (<it>b </it>= 0.135, <it>p < 0.01</it>) were identified as significant direct predictors of the turnover intention of physicians, with 41.2% of the variance explained unitedly, under the control of sociodemographic variables, among which gender, age, and years of service were always significant. However, job-itself satisfaction no longer became significant, with the estimated parameter on job rewards satisfaction smaller after burnout syndrome variables were included. As congregated latent concepts, job satisfaction had both significant direct effects (gamma₂₁= -0.32, <it>p < 0.01</it>) and indirect effects (gamma₁₁× beta₂₁= -0.13, <it>p < 0.01</it>) through occupational burnout (62% explained) as a mediator on turnover intention (47% explained).</p> <p>Conclusions</p> <p>Our study reveals that several, but not all dimensions of both job satisfaction and burnout syndrome are relevant factors affecting physicians' turnover intention, and there may be partial mediation effects of occupational burnout, mainly through emotional exhaustion, within the impact of job satisfaction on turnover intention. This suggests that enhancements in job satisfaction can be expected to reduce physicians' intentions to quit by the intermediary role of burnout as well as the direct path. It is hoped that these findings will offer some clues for health-sector managers to keep their physician resource motivated and stable.</p

Computational Prediction of Intronic microRNA Targets using Host Gene Expression Reveals Novel Regulatory Mechanisms

Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes

Integration of Transcriptomics, Proteomics, and MicroRNA Analyses Reveals Novel MicroRNA Regulation of Targets in the Mammalian Inner Ear

We have employed a novel approach for the identification of functionally important microRNA (miRNA)-target interactions, integrating miRNA, transcriptome and proteome profiles and advanced in silico analysis using the FAME algorithm. Since miRNAs play a crucial role in the inner ear, demonstrated by the discovery of mutations in a miRNA leading to human and mouse deafness, we applied this approach to microdissected auditory and vestibular sensory epithelia. We detected the expression of 157 miRNAs in the inner ear sensory epithelia, with 53 miRNAs differentially expressed between the cochlea and vestibule. Functionally important miRNAs were determined by searching for enriched or depleted targets in the transcript and protein datasets with an expression consistent with the dogma of miRNA regulation. Importantly, quite a few of the targets were detected only in the protein datasets, attributable to regulation by translational suppression. We identified and experimentally validated the regulation of PSIP1-P75, a transcriptional co-activator previously unknown in the inner ear, by miR-135b, in vestibular hair cells. Our findings suggest that miR-135b serves as a cellular effector, involved in regulating some of the differences between the cochlear and vestibular hair cells