Search

Your search keyword '"Correia, Catarina"' showing total 10 results
Start Over Author "Correia, Catarina" Topic autistic disorder
10 results on '"Correia, Catarina"'

1. Protein interaction networks reveal novel autism risk genes within GWAS statistical noise.

Author

Correia C, Oliveira G, and Vicente AM

Subjects
Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Models, Statistical, Autistic Disorder genetics, Computational Biology methods, Protein Interaction Maps
Abstract

Genome-wide association studies (GWAS) for Autism Spectrum Disorder (ASD) thus far met limited success in the identification of common risk variants, consistent with the notion that variants with small individual effects cannot be detected individually in single SNP analysis. To further capture disease risk gene information from ASD association studies, we applied a network-based strategy to the Autism Genome Project (AGP) and the Autism Genetics Resource Exchange GWAS datasets, combining family-based association data with Human Protein-Protein interaction (PPI) data. Our analysis showed that autism-associated proteins at higher than conventional levels of significance (P<0.1) directly interact more than random expectation and are involved in a limited number of interconnected biological processes, indicating that they are functionally related. The functionally coherent networks generated by this approach contain ASD-relevant disease biology, as demonstrated by an improved positive predictive value and sensitivity in retrieving known ASD candidate genes relative to the top associated genes from either GWAS, as well as a higher gene overlap between the two ASD datasets. Analysis of the intersection between the networks obtained from the two ASD GWAS and six unrelated disease datasets identified fourteen genes exclusively present in the ASD networks. These are mostly novel genes involved in abnormal nervous system phenotypes in animal models, and in fundamental biological processes previously implicated in ASD, such as axon guidance, cell adhesion or cytoskeleton organization. Overall, our results highlighted novel susceptibility genes previously hidden within GWAS statistical "noise" that warrant further analysis for causal variants.

Published
2014
Full Text
View/download PDF

2. A genome-wide scan for common alleles affecting risk for autism.

Author

Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, and Hallmayer J

Subjects
Alleles, DNA Copy Number Variations, Databases, Genetic, Genetic Variation, Genome, Human, Genotype, Humans, Risk Factors, White People genetics, Autistic Disorder genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Published
2010
Full Text
View/download PDF

3. Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: genetic and molecular studies.

Author

Tansey KE, Brookes KJ, Hill MJ, Cochrane LE, Gill M, Skuse D, Correia C, Vicente A, Kent L, Gallagher L, and Anney RJL

Subjects
Genotype, Humans, Polymorphism, Single Nucleotide, White People genetics, Autistic Disorder genetics, Genetic Predisposition to Disease, Receptors, Oxytocin genetics
Abstract

Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n=436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples., (2010 Elsevier Ireland Ltd. All rights reserved.)

Published
2010
Full Text
View/download PDF

4. Association of the alpha4 integrin subunit gene (ITGA4) with autism.

Author

Correia C, Coutinho AM, Almeida J, Lontro R, Lobo C, Miguel TS, Martins M, Gallagher L, Conroy J, Gill M, Oliveira G, and Vicente AM

Subjects
Autistic Disorder etiology, Autistic Disorder immunology, Autoantibodies blood, Brain immunology, Chromosomes, Human, Pair 2, Family Health, Genetic Linkage, Genetic Markers, Humans, Neurogenic Inflammation, Neuroimmunomodulation, Polymorphism, Single Nucleotide, Autistic Disorder genetics, Genetic Association Studies, Integrin alpha4 genetics
Abstract

In the present work, we provide further evidence for the involvement of the integrin alpha-4 precursor gene (ITGA4) in the etiology of autism, by replicating previous findings of a genetic association with autism in various independent populations. The ITGA4 gene maps to the autism linkage region on 2q31-33 and is therefore a plausible positional candidate. We tested eight single nucleotide polymorphisms (SNPs) in the ITGA4 gene region for association with autism in a sample of 164 nuclear families. Evidence for association was found for the rs155100 marker (P = 0.019) and for a number of specific marker haplotypes containing this SNP (0.00053 < P < 0.022). alpha4 integrins are known to play a key role in neuroinflammatory processes, which are hypothesized to contribute to autism. In this study, an association was found between the ITGA4 rs1449263 marker and levels of a serum autoantibody directed to brain tissue, which was previously shown to be significantly more frequent in autistic patients than in age-matched controls in our population. This result suggests that the ITGA4 gene could be involved in a neuroimmune process thought to occur in autistic patients and, together with previous findings, offers a new perspective on the role of integrins in the etiology of autism to which little attention has been paid so far., (2009 Wiley-Liss, Inc.)

Published
2009
Full Text
View/download PDF

5. MECP2 coding sequence and 3'UTR variation in 172 unrelated autistic patients.

Author

Coutinho AM, Oliveira G, Katz C, Feng J, Yan J, Yang C, Marques C, Ataíde A, Miguel TS, Borges L, Almeida J, Correia C, Currais A, Bento C, Mota-Vieira L, Temudo T, Santos M, Maciel P, Sommer SS, and Vicente AM

Subjects
Adolescent, Alanine genetics, Case-Control Studies, Child, Child, Preschool, DNA Mutational Analysis, Exons genetics, Female, Gene Expression Regulation, Glycine genetics, Humans, Introns genetics, Male, Methyl-CpG-Binding Protein 2 metabolism, Mutation, Missense genetics, Pedigree, RNA, Messenger genetics, RNA, Messenger metabolism, X Chromosome Inactivation genetics, 3' Untranslated Regions genetics, Autistic Disorder genetics, Methyl-CpG-Binding Protein 2 genetics, Open Reading Frames genetics
Abstract

Mutations in the coding sequence of the methyl-CpG-binding protein 2 gene (MECP2), which cause Rett syndrome (RTT), have been found in male and female autistic subjects without, however, a causal relation having unequivocally been established. In this study, the MECP2 gene was scanned in a Portuguese autistic population, hypothesizing that the phenotypic spectrum of mutations extends beyond the traditional diagnosis of RTT and X-linked mental retardation, leading to a non-lethal phenotype in male autistic patients. The coding region, exon-intron boundaries, and the whole 3'UTR were scanned in 172 patients and 143 controls, by Detection of Virtually All Mutations-SSCP (DOVAM-S). Exon 1 was sequenced in 103 patients. We report 15 novel variants, not found in controls: one missense, two intronic, and 12 in the 3'UTR (seven in conserved nucleotides). The novel missense change, c.617G > C (p.G206A), was present in one autistic male with severe mental retardation and absence of language, and segregates in his maternal family. This change is located in a highly conserved residue within a region involved in an alternative transcriptional repression pathway, and likely alters the secondary structure of the MeCP2 protein. It is therefore plausible that it leads to a functional modification of MeCP2. MECP2 mRNA levels measured in four patients with 3'UTR conserved changes were below the control range, suggesting an alteration in the stability of the transcripts. Our results suggest that MECP2 can play a role in autism etiology, although very rarely, supporting the notion that MECP2 mutations underlie several neurodevelopmental disorders., ((c) 2007 Wiley-Liss, Inc.)

Published
2007
Full Text
View/download PDF

6. Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.

Author

Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, Bento C, Marques C, Ataíde A, Miguel TS, Moore JH, Oliveira G, and Vicente AM

Subjects
Adolescent, Autistic Disorder etiology, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Linkage Disequilibrium, Male, Autistic Disorder genetics, Blood Platelets metabolism, Epistasis, Genetic, Integrin beta3 genetics, Serotonin metabolism, Serotonin Plasma Membrane Transport Proteins genetics
Abstract

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.

Published
2007
Full Text
View/download PDF

7. Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene.

Author

Correia C, Coutinho AM, Diogo L, Grazina M, Marques C, Miguel T, Ataíde A, Almeida J, Borges L, Oliveira C, Oliveira G, and Vicente AM

Subjects
Autistic Disorder epidemiology, Autistic Disorder metabolism, Chromosome Mapping, DNA Mutational Analysis, DNA Primers genetics, Gene Expression genetics, Gene Frequency, Haplotypes, Humans, Lactic Acid blood, Mitochondrial Diseases epidemiology, Mitochondrial Membrane Transport Proteins, Pyruvic Acid blood, Aspartic Acid genetics, Aspartic Acid metabolism, Autistic Disorder genetics, DNA, Mitochondrial genetics, Glutamic Acid genetics, Membrane Transport Proteins genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases physiopathology, Mitochondrial Proteins genetics
Abstract

In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.

Published
2006
Full Text
View/download PDF

8. Autoantibody repertoires to brain tissue in autism nuclear families.

Author

Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, and Vicente AM

Subjects
Adolescent, Blotting, Western, Child, Child, Preschool, Female, Humans, Male, Myelin Basic Protein immunology, Autistic Disorder genetics, Autistic Disorder immunology, Autoantibodies blood, Brain immunology, Nuclear Family
Abstract

The hypothesis of an immune dysfunction in autism spectrum disorders has previously been put forward without, however, compelling evidence of a direct relation to its etiology or pathogenesis. To further understand if autoimmunity could play a significant role in autism, we analyzed autoantibody repertoires to brain tissue extract in the plasma of 171 autism children, their parents, and 54 controls, by quantitative immunoblotting. Multiparametric analysis revealed significant differences between patients and controls, and showed that one single reactivity in Section 32 of the blot had the most power to discriminate between these samples. Family correlation coefficients and heritability estimates did not provide any evidence that this reactivity was genetically determined. While the molecular weight of the target protein suggested that it might be an isoform of Myelin Basic Protein (MBP), inhibition assays with human MBP argued against this hypothesis. The study evidences the widespread occurrence of autoreactivities to brain tissue in autism patients, which may represent the immune system's neuroprotective response to a previous brain injury occurred during neurodevelopment. The molecular identification of the target protein in Section 32 will contribute to the understanding of the role of immune responses against brain antigens in autistic patients.

Published
2004
Full Text
View/download PDF

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

Author

Hadley, Dexter, Wu, Zhi Liang, Kao, Charlly, Kini, Akshata, Mohamed-Hadley, Alisha, Thomas, Kelly, Vazquez, Lyam, Qiu, Haijun, Mentch, Frank, Pellegrino, Renata, Kim, Cecilia, Connolly, John, Pinto, Dalila, Merikangas, Alison, Klei, Lambertus, Vorstman, Jacob, Thompson, Ann, Regan, Regina, Pagnamenta, Alistair, Oliveira, Barbara, Magalhaes, Tiago, Gilbert, John, Duketis, Eftichia, De Jonge, Maretha, Cuccaro, Michael, Correia, Catarina, Conroy, Judith, Conceição, Inês, Chiocchetti, Andreas, Casey, Jillian, Bolshakova, Nadia, Bacchelli, Elena, Anney, Richard, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wallace, Simon, Van Engeland, Herman, Soorya, Latha, Rogé, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy, Mcgrew, Susan, Lord, Catherine, Leboyer, Marion, Le Couteur, Ann, Kolevzon, Alexander, Jacob, Suma, Guter, Stephen, Green, Jonathan, Green, Andrew, Gillberg, Christopher, Fernandez, Bridget, Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick, Bölte, Sven, Bernier, Raphael, Baird, Gillian, Bailey, Anthony, Anagnostou, Evdokia, Almeida, Joana, Wijsman, Ellen, Vieland, Veronica, Vicente, Astrid, Schellenberg, Gerard, Pericak-Vance, Margaret, Paterson, Andrew, Parr, Jeremy, Oliveira, Guiomar, Nurnberger, John, Monaco, Anthony, Maestrini, Elena, Klauck, Sabine, Haines, Jonathan, Geschwind, Daniel, Freitag, Christine, Folstein, Susan, Ennis, Sean, Coon, Hilary, Battaglia, Agatino, Szatmari, Peter, Sutcliffe, James, Hallmayer, Joachim, Gill, Michael, Cook, Edwin, Buxbaum, Joseph, Devlin, Bernie, Gallagher, Louise, Betancur, Catalina, Scherer, Stephen, Glessner, Joseph, Hakonarson, Hakon, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Psychiatry, Department of Genetics and Genomic Sciences, The Mindich Child Health and Development Institute, The Icahn Institute for Genomics and Multiscale Biology, Friedman Brain Institute, Discipline of Psychiatry [Dublin], School of Medicine [Dublin], Trinity College Dublin-Trinity College Dublin, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), National Children's Research Centre, Our Lady's Children's Hospital, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Center for Biodiversity, Functional & Integrative Genomics, Universidade de Lisboa (ULISBOA), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Children's University Hospital, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Pediatrics, University of Alberta, School of Education, University of Birmingham [Birmingham], University of Oxford [Oxford]-Warneford Hospital, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Institute for Biomedical Imaging and Life Science, University of Coimbra [Portugal] (UC), Vanderbilt University [Nashville], Center for Autism and the Developing Brain (CADB), Weill Medical College of Cornell University [New York], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Foundation Fondamental, Institute of Health and Society, Newcastle University [Newcastle], Institute for Juvenile Research and Department of Psychiatry, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Manchester Academic Health Sciences Centre, Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], National Centre for Medical Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Université Paris Diderot - Paris 7 (UPD7), Institute of Psychiatry, King‘s College London, Department of Child and Adolescent Psychiatry, Institute of psychiatry, University of Washington [Seattle], Paediatric Neurodisability, King‘s College London-King's Health Partners, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, University of British Columbia (UBC), Bloorview Research Institute, University of Toronto, Division of Medical Genetics [Seattle], Departments of Biostatistics and Medicine, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Institute of Neuroscience [Newcastle] (ION), Indiana University School of Medicine, Indiana University System-Indiana University System, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Utah Autism Research Program, University of Utah Psychiatry Department, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Neuroscience, Trinity College Dublin-St. James's Hospital, Institute for Juvenile Research, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), McLaughlin Centre, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), The study was funded by an Institutional Development Fund from The Children's Hospital of Philadelphia, The Margaret Q Landenberger Foundation, The Lurie Family Foundation, The Kubert Estate Fund and by U01HG005830. AGRE is a program of Autism Speaks and is at present supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere (PI) and formerly by grant MH64547 to D.H. Geschwind (PI)., Universidade de Lisboa = University of Lisbon (ULISBOA), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Betancur, Catalina, University of Oxford, University of Oxford-Warneford Hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Neuroscience Paris Seine (NPS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, DNA Copy Number Variations, Gene regulatory network, Druggability, General Physics and Astronomy, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Receptors, Metabotropic Glutamate, General Biochemistry, Genetics and Molecular Biology, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, 0302 clinical medicine, Calmodulin, medicine, Gene family, Humans, Gene Regulatory Networks, Autistic Disorder, Child, Gene, 030304 developmental biology, Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, General Chemistry, medicine.disease, 3. Good health, Metabotropic glutamate receptor, Schizophrenia, Child, Preschool, Autism, Female, Metabotropic glutamate receptor 3, 030217 neurology & neurosurgery
Abstract

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., The autism spectrum disorders are complex genetic traits characterized by various neurodevelopmental deficits. Here, the authors analyse defective gene family interaction networks in autism cases and healthy controls and identify potential gene family interactions that may contribute to autism aetiology.

Published
2014

10. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, and Posey, David J

Subjects
Genotype, DNA Copy Number Variations, Autism, Intellectual and Developmental Disabilities (IDD), European Continental Ancestry Group, Medical and Health Sciences, Databases, Genetic, Clinical Research, Risk Factors, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Aetiology, Autistic Disorder, Polymorphism, Alleles, Pediatric, Genetics & Heredity, Genome, Whites, Prevention, Human Genome, Genetic Variation, Single Nucleotide, Biological Sciences, Brain Disorders, Mental Health, Biotechnology, Human, Genome-Wide Association Study
Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results