Internal quantum efficiency of AlGaN/AlN quantum dot superlattices for electron-pumped ultraviolet sources.

In this paper, we describe the growth and characterization of ≈530 nm thick superlattices (100 periods) of AlxGa1-xN/AlN (0 ⩽ x ⩽ 0.1) Stranski-Krastanov quantum dots (QDs) for application as the active region of electron-beam pumped ultraviolet lamps. Highly dense (>1011 cm-2) QD layers are deposited by molecular beam epitaxy, and we explore the effect of the III/V ratio during the growth process on their optical performance. The study considers structures emitting in the 244-335 nm range at room temperature, with a relative linewidth in the 6%-11% range, mainly due to the QD diameter dispersion inherent in self-assembled growth. Under electron pumping, the emission efficiency remains constant for acceleration voltages below ≈9 kV. The correlation of this threshold with the total thickness of the SL and the penetration depth of the electron beam confirms the homogeneity of the nanostructures along the growth axis. Below the threshold, the emission intensity scales linearly with the injected current. The internal quantum efficiency (IQE) is characterized at low injection, which reveals the material properties in terms of non-radiative processes, and high injection, which emulates carrier injection in operation conditions. In QDs synthesized with III/V ratio <0.75, the IQE remains around 50% from low injection to pumping power densities as high as 200 kW cm-2, being the first kind of nanostructure that present such stable behaviour.

Assessment of AlGaN/AlN superlattices on GaN nanowires as active region of electron-pumped ultraviolet sources.

In this paper, we describe the design and characterization of 400 nm long (88 periods) Al x Ga1-x N/AlN (0 ≤ x ≤ 0.1) quantum dot superlattices deposited on self-assembled GaN nanowires for application in electron-pumped ultraviolet sources. The optical performance of GaN/AlN superlattices on nanowires is compared with the emission of planar GaN/AlN superlattices with the same periodicity and thickness grown on bulk GaN substrates along the N-polar and metal-polar crystallographic axes. The nanowire samples are less sensitive to nonradiative recombination than planar layers, attaining internal quantum efficiencies (IQE) in excess of 60% at room temperature even under low injection conditions. The IQE remains stable for higher excitation power densities, up to 50 kW cm-2. We demonstrate that the nanowire superlattice is long enough to collect the electron-hole pairs generated by an electron beam with an acceleration voltage V A = 5 kV. At such V A, the light emitted from the nanowire ensemble does not show any sign of quenching under constant electron beam excitation (tested for an excitation power density around 8 kW cm-2 over the scale of minutes). Varying the dot/barrier thickness ratio and the Al content in the dots, the nanowire peak emission can be tuned in the range from 340 to 258 nm.

Giant, Voltage Tuned, Quality Factors of Single Wall Carbon Nanotubes and Graphene at Room Temperature.

Mastering dissipation in graphene-based nanostructures is still the major challenge in most fundamental and technological exploitations of these ultimate mechanical nanoresonators. Although high quality factors have been measured for carbon nanotubes (>106) and graphene (>105) at cryogenic temperatures, room-temperature values are orders of magnitude lower (≃102). We present here a controlled quality factor increase of up to ×103 for these basic carbon nanostructures when externally stressed like a guitar string. Quantitative agreement is found with theory attributing this decrease in dissipation to the decrease in viscoelastic losses inside the material, an effect enhanced by tunable "soft clamping". Quality factors exceeding 25 000 for SWCNTs and 5000 for graphene were obtained on several samples, reaching the limits of the graphene material itself. The combination of ultralow size and mass with high quality factors opens new perspectives for atomically localized force sensing and quantum computing as the coherence time exceeds state-of-the-art cryogenic devices.

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/ß-catenin signaling.

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/ß-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/ß-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/ß-catenin pathway.

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity.

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.

Determining the composition of the vacuum-liquid interface in ionic-liquid mixtures.

The vacuum-liquid interfaces of a number of ionic-liquid mixtures have been investigated using the combination of reactive-atom scattering with laser-induced fluorescence detection (RAS-LIF), selected surface tension measurements, and molecular dynamics (MD) simulations. The mixtures are based on the widespread 1-alkyl-3-methylimidazolium ([Cnmim]+) cation, including mixed cations which differ in chain length or chemical functionality with a common anion; and different anions for a common cation. RAS-LIF results imply that the surface compositions exhibit a general form of non-stoichiometric behaviour that mimics the well-known Henry's and Raoult's laws at low and high mole fraction, respectively. The extended Langmuir model provides a moderately good single-parameter fit, but higher-order terms are required for an accurate description. The quantitative relationship between RAS-LIF and surface tension, which probes the surface composition only indirectly, is explored for mixtures of [C2mim]+ and [C12mim]+ with a common bis(trifluoromethylsulfonyl)imide ([NTf2]-) anion. Extended Langmuir model fits to surface tension data are broadly consistent with those to RAS-LIF; however, several other common approaches to extracting surface compositions from measured surface tensions result in much larger discrepancies. MD simulations suggest that RAS-LIF faithfully reports on the alkyl-chain exposure at the surface, which is only subtly modified by composition-dependent structural reorganisation.

Copy number variation in schizophrenia in Sweden.

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.

Ultrashort single-wall carbon nanotubes reveal field-emission coulomb blockade and highest electron-source brightness.

We present here well-defined Coulomb staircases using an original field-emission experiment on several individual in situ-grown single-wall carbon nanotubes. A unique in situ process was applied nine times to progressively shorten one single-wall carbon nanotube down to ≃10 nm, which increased the oscillations periods from 5.5 to 80 V, the temperature for observable Coulomb staircase to 1100 K and the currents to 1.8 µA. This process led to the brightest electron source ever reported [9×1011 A/(str m2 V)].

Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample.

Although copy number variants (CNVs) are important in genomic medicine, CNVs have not been systematically assessed for many complex traits. Several large rare CNVs increase risk for schizophrenia (SCZ) and autism and often demonstrate pleiotropic effects; however, their frequencies in the general population and other complex traits are unknown. Genotyping large numbers of samples is essential for progress. Large cohorts from many different diseases are being genotyped using exome-focused arrays designed to detect uncommon or rare protein-altering sequence variation. Although these arrays were not designed for CNV detection, the hybridization intensity data generated in each experiment could, in principle, be used for gene-focused CNV analysis. Our goal was to evaluate the extent to which CNVs can be detected using data from one particular exome array (the Illumina Human Exome Bead Chip). We genotyped 9100 Swedish subjects (3962 cases with SCZ and 5138 controls) using both standard genome-wide association study (GWAS) and exome arrays. In comparison with CNVs detected using GWAS arrays, we observed high sensitivity and specificity for detecting genic CNVs 400 kb including known pathogenic CNVs along with replicating the literature finding that cases with SCZ had greater enrichment for genic CNVs. Our data confirm the association of SCZ with 16p11.2 duplications and 22q11.2 deletions, and suggest a novel association with deletions at 11q12.2. Our results suggest the utility of exome-focused arrays in surveying large genic CNVs in very large samples; and thereby open the door for new opportunities such as conducting well-powered CNV assessment and comparisons between different diseases. The use of a single platform also minimizes potential confounding factors that could impact accurate detection.

Association at SYNE1 in both bipolar disorder and recurrent major depression.

Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10⁻7, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10⁻8, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.

Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder.

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.

Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample.

We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.

Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.

The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.

Ultra low power consumption for self-oscillating nanoelectromechanical systems constructed by contacting two nanowires.

We report here the observation of a new self-oscillation mechanism in nanoelectromechanical systems (NEMS). A highly resistive nanowire was positioned to form a point-contact at a chosen vibration node of a silicon carbide nanowire resonator. Spontaneous and robust mechanical oscillations arise when a sufficient DC voltage is applied between the two nanowires. An original model predicting the threshold voltage is used to estimate the piezoresistivity of the point-contact in agreement with the observations. The measured input power is in the pW-range which is the lowest reported value for such systems. The simplicity of the contacting procedure and the low power consumption open a new route for integrable and low-loss self-excited NEMS devices.

Mapping neurodevelopment with sleep macro- and micro-architecture across multiple pediatric populations.

Profiles of sleep duration and timing and corresponding electroencephalographic activity reflect brain changes that support cognitive and behavioral maturation and may provide practical markers for tracking typical and atypical neurodevelopment. To build and evaluate a sleep-based, quantitative metric of brain maturation, we used whole-night polysomnography data, initially from two large National Sleep Research Resource samples, spanning childhood and adolescence (total N = 4,013, aged 2.5 to 17.5 years): the Childhood Adenotonsillectomy Trial (CHAT), a research study of children with snoring without neurodevelopmental delay, and Nationwide Children's Hospital (NCH) Sleep Databank, a pediatric sleep clinic cohort. Among children without neurodevelopmental disorders (NDD), sleep metrics derived from the electroencephalogram (EEG) displayed robust age-related changes consistently across datasets. During non-rapid eye movement (NREM) sleep, spindles and slow oscillations further exhibited characteristic developmental patterns, with respect to their rate of occurrence, temporal coupling and morphology. Based on these metrics in NCH, we constructed a model to predict an individual's chronological age. The model performed with high accuracy (r = 0.93 in the held-out NCH sample and r = 0.85 in a second independent replication sample - the Pediatric Adenotonsillectomy Trial for Snoring (PATS)). EEG-based age predictions reflected clinically meaningful neurodevelopmental differences; for example, children with NDD showed greater variability in predicted age, and children with Down syndrome or intellectual disability had significantly younger brain age predictions (respectively, 2.1 and 0.8 years less than their chronological age) compared to age-matched non-NDD children. Overall, our results indicate that sleep architectureoffers a sensitive window for characterizing brain maturation, suggesting the potential for scalable, objective sleep-based biomarkers to measure neurodevelopment.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain.

It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. As only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among single-nucleotide polymorphisms (SNPs) selected for marginal evidence for association (P<0.5) from genome-wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs, which are also expression quantitative trait loci (eQTLs), should carry more true association signals compared with SNPs that are not marginally associated. To test this, we identified marginally associated (P<0.5) SNPs from two of the largest available schizophrenia GWAS data sets. We assigned eQTL status to those SNPs based upon an eQTL data set derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can, in principle, allow relevant susceptibility eQTLs to be identified.

Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia.

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.

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.

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.

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.

A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10⁻6. This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10⁻6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10⁻8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.