Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology

Clinical and polysomnographic course of childhood narcolepsy with cataplexy.

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e., brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns.

Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/alpha-melanocyte-stimulating hormone (NEI/alphaMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG theta-power in the active phase. We suggest that NEI/alphaMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal

Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort.

OBJECTIVES: Sleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort. METHODS: Data from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22 years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N = 155 AA cases and 2598 AA controls; N = 512 EA cases and 4250 EA controls). RESULTS: Lifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth. CONCLUSION: The present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak

Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection

Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype.

OBJECTIVE: Sex differences in the brain are traditionally treated as binary. We present new evidence that a continuous measure of sex differentiation of the brain can explain sex differences in psychopathology. The degree of sex-differentiated brain features (ie, features that are more common in one sex) may predispose individuals toward sex-biased psychopathology and may also be influenced by the genome. We hypothesized that individuals with a female-biased differentiation score would have greater female-biased psychopathology (internalizing symptoms, such as anxiety and depression), whereas individuals with a male-biased differentiation score would have greater male-biased psychopathology (externalizing symptoms, such as disruptive behaviors). METHOD: Using the Philadelphia Neurodevelopmental Cohort database acquired from database of Genotypes and Phenotypes, we calculated the sex differentiation measure, a continuous data-driven calculation of each individuals degree of sex-differentiating features extracted from multimodal brain imaging data (magnetic resonance imaging [MRI] /diffusion MRI) from the imaged participants (n&nbsp;= 866, 407 female and 459 male). RESULTS: In male individuals, higher differentiation scores were correlated with higher levels of externalizing symptoms (r&nbsp;= 0.119, p&nbsp;= .016). The differentiation measure reached genome-wide association study significance (p&nbsp;&lt; 5∗10-8) in male individuals with single nucleotide polymorphisms Chromsome5:rs111161632:RASGEF1C and Chromosome19:rs75918199:GEMIN7, and in female individuals with Chromosome2:rs78372132:PARD3B and Chromosome15:rs73442006:HCN4. CONCLUSION: The sex differentiation measure provides an initial topography of quantifying male and female brain features. This demonstration that the sex of the human brain can be conceptualized on a continuum has implications for both the presentation of psychopathology and the relation of the brain with genetic variants that may be associated with brain differentiation

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

International audienceAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions