Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We ...tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.
By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we ...identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10
). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) ...of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.
Sleep spindles are characteristic electroencephalogram (EEG) signatures of stage 2 non-rapid eye movement sleep. Implicated in sleep regulation and cognitive functioning, spindles may represent ...heritable biomarkers of neuropsychiatric disease. Here we characterize spindles in 11,630 individuals aged 4 to 97 years, as a prelude to future genetic studies. Spindle properties are highly reliable but exhibit distinct developmental trajectories. Across the night, we observe complex patterns of age- and frequency-dependent dynamics, including signatures of circadian modulation. We identify previously unappreciated correlates of spindle activity, including confounding by body mass index mediated by cardiac interference in the EEG. After taking account of these confounds, genetic factors significantly contribute to spindle and spectral sleep traits. Finally, we consider topographical differences and critical measurement issues. Taken together, our findings will lead to an increased understanding of the genetic architecture of sleep spindles and their relation to behavioural and health outcomes, including neuropsychiatric disorders.
The CORNISH project is the highest resolution radio continuum survey of the Galactic plane to date. It is the 5 GHz radio continuum part of a series of multi-wavelength surveys that focus on the ...northern GLIMPSE region (10degrees < l < 65degrees), observed by the Spitzer satellite in the mid-infrared. Observations with the Very Large Array in B and BnA configurations have yielded a 1".5 resolution Stokes I map with a root mean square noise level better than 0.4 mJy beam super(-1). Here we describe the data-processing methods and data characteristics, and present a new, uniform catalog of compact radio emission. This includes an implementation of automatic deconvolution that provides much more reliable imaging than standard CLEANing. A rigorous investigation of the noise characteristics and reliability of source detection has been carried out. We show that the survey is optimized to detect emission on size scales up to 14" and for unresolved sources the catalog is more than 90% complete at a flux density of 3.9 mJy. We have detected 3062 sources above a 7sigma detection limit and present their ensemble properties. The catalog is highly reliable away from regions containing poorly sampled extended emission, which comprise less than 2% of the survey area. Imaging problems have been mitigated by down-weighting the shortest spacings and potential artifacts flagged via a rigorous manual inspection with reference to the Spitzer infrared data. We present images of the most common source types found: H II regions, planetary nebulae, and radio galaxies. The CORNISH data and catalog are available online at http://cornish.leeds.ac.uk.
Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent ...exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving coexpression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in the capacity of GIT1-R283W to stimulate PAK phosphorylation in cultured hippocampal neurons. In addition, GIT1-R283W showed deficits in the induction of GAD1 (glutamate decarboxylase 1) protein expression. Extending these functional assays to 10 additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss of function toward MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.
Several genome-wide association studies for bipolar disorder (BD) have found a strong association of the Ankyrin 3 (ANK3) gene. This association spans numerous linked single-nucleotide polymorphisms ...(SNPs) in an ~250-kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of the six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as Ankyrin-G. Using RNA ligase-mediated rapid amplification of cDNA ends to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites and coupling of specific 5' ends with 3' mRNA splicing events in postmortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD-associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 that may be relevant to BD pathophysiology.
ABSTRACT We describe the motivation, design, and implementation of the CORNISH survey, an arcsecond-resolution radio continuum survey of the inner galactic plane at 5 GHz using the Very Large Array ...(VLA). It is a blind survey coordinated with the northern Spitzer GLIMPSE I region covering 10° < l < 65° and |b| < 1° at similar resolution. We discuss in detail the strategy that we employed to control the shape of the synthesised beam across this survey, which covers a wide range of fairly low declinations. Two snapshots separated by 4h kept the beam elongation to less that 1.5 over 75% of the survey area and less than 2 over 98% of the survey. The prime scientific motivation is to provide an unbiased survey for ultra-compact H II regions to study this key phase in massive star formation. A sensitivity around 2 mJy will allow the automatic distinction between radio-loud and radio-quiet mid-IR sources found in the Spitzer surveys. This survey has many legacy applications beyond star formation, including evolved stars, active stars and binaries, and extragalactic sources. The CORNISH survey for compact ionized sources complements other Galactic plane surveys that target diffuse and nonthermal sources, as well as atomic and molecular phases to build up a complete picture of the interstellar medium in the Galaxy.
To conduct a meta-analytic review of HIV interventions for people living with HIV (PLWH) to determine their overall efficacy in reducing HIV risk behaviours and identify intervention characteristics ...associated with efficacy.
Comprehensive searches included electronic databases from 1988 to 2004, hand searches of journals, reference lists of articles, and contacts with researchers. Twelve trials met the stringent selection criteria: randomization or assignment with minimal bias, use of statistical analysis, and assessment of HIV-related behavioural or biologic outcomes at least 3 months after the intervention. Random-effects models were used to aggregate data.
Interventions significantly reduced unprotected sex odds ratio (OR), 0.57; 95% confidence interval (CI) 0.40-0.82 and decreased acquisition of sexually transmitted diseases (OR, 0.20; 95% CI, 0.05-0.73). Non-significant intervention effects were observed for needle sharing (OR, 0.47, 95% CI, 0.13-1.71). As a whole, interventions with the following characteristics significantly reduced sexual risk behaviours: (1) based on behavioural theory; (2) designed to change specifically HIV transmission risk behaviours; (3) delivered by health-care providers or counsellors; (4) delivered to individuals; (5) delivered in an intensive manner; (6) delivered in settings where PLWH receive routine services or medical care; (7) provided skills building, or (8) addressed a myriad of issues related to mental health, medication adherence, and HIV risk behaviour.
Interventions targeting PWLH are efficacious in reducing unprotected sex and acquisition of sexually transmitted diseases. Efficacious strategies identified in this review should be incorporated into community HIV prevention efforts and further evaluated for effectiveness.
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