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

Author

Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.

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 3 10-28. 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 × 10-28 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. © The Author 2010. Published by Oxford University Press. All rights reserved.

Published
2010

2. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.

Subjects
mental disorders
Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (

Published
2010

3. Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT

Author

Reichert Jennifer G, Nakamine Alisa, Cohen Ninette, Goldsmith Juliet E, Edelmann Lisa, Cai Guiqing, Hoffman Ellen J, Zurawiecki Danielle M, Silverman Jeremy M, Hollander Eric, Soorya Latha, Anagnostou Evdokia, Betancur Catalina, and Buxbaum Joseph D

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications. Methods In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region. Results MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003). Conclusion MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.

Published
2008
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4. Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Author

Naisha Shah, William M. McMahon, Barbara Parrini, Jeremy R. Parr, Thomas Bourgeron, Vanessa Hus, Gudrun Nygren, Sabine M. Klauck, John B. Vincent, Nadine M. Melhem, Jillian P. Casey, Christina Corsello, Jonathan L. Haines, Andrew D. Paterson, Raffaella Tancredi, Alistair T. Pagnamenta, Jonathan Green, Richard Delorme, Geraldine Dawson, Andrew Pickles, Carine Mantoulan, Alexander Kolevzon, Bridget A. Fernandez, Frederico Duque, Inês Sousa, Tara Paton, Kathryn Roeder, Joana Almeida, Richard Anney, Margaret A. Pericak-Vance, Joachim Hallmayer, Gerard D. Schellenberg, Sabata C. Lund, Rita M. Cantor, Daniel H. Geschwind, Janine A. Lamb, Annette Estes, Sven Bölte, Hakon Hakonarson, Gillian Hughes, Gillian Baird, John I. Nurnberger, Jessica Brian, Bernie Devlin, Roberta Igliozzi, Vera Stoppioni, Jiannis Ragoussis, Peter Szatmari, Ghazala Mirza, Eric Fombonne, Thomas H. Wassink, Emily L. Crawford, Nuala Sykes, Danielle Zurawiecki, Graham Kenny, David J. Posey, Elena Maestrini, Vlad Kustanovich, Elena Bacchelli, Veronica J. Vieland, Stephen W. Scherer, Guiomar Oliveira, Simon Wallace, John R. Gilbert, Latha Soorya, Sean Brennan, Tiago R. Magalhaes, Hilary Coon, Elizabeth A. Heron, Sabine Schlitt, Fritz Poustka, Astrid M. Vicente, Patrick Bolton, Linda Lotspeich, Nancy J. Minshew, Val C. Sheffield, Bennett L. Leventhal, Xiao-Qing Liu, Andrew Green, Joseph D. Buxbaum, Shawn Wood, Susan E. Folstein, Sean Ennis, Catarina Correia, James S. Sutcliffe, Carolyn Noakes, Ann Le Couteur, Marion Leboyer, Ann P. Thompson, Christine M. Freitag, Fred R. Volkmar, Katerina Papanikolaou, Dalila Pinto, Agatino Battaglia, Frances Lombard, Joseph Piven, Maretha de Jonge, Michael Rutter, Clara Lajonchere, Kerstin Wittemeyer, Herman van Engeland, Michael L. Cuccaro, Richard Holt, Lonnie Zwaigenbaum, Louise Gallagher, Jeff Munson, Ana Tryfon, John Tsiantis, Lambertus Klei, Christopher Gillberg, Penny Farrar, Joseph T. Glessner, Ellen M. Wijsman, Anthony P. Monaco, Wendy Roberts, Nadia Bolshakova, Cecilia Kim, Judith Miller, Stephen J. Guter, Susanne Thomson, Catherine Lord, Anthony J. Bailey, Miriam Law-Smith, Michael Gill, Christopher J. McDougle, Bernadette Rogé, Alison K. Merikangas, Jacob A. S. Vorstman, Suma Jacob, Judith Conroy, Kirsty Wing, Regina Regan, Jennifer L. Howe, Stanley F. Nelson, Edwin H. Cook, Catalina Betancur, Eftichia Duketis, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Centre for Applied Genomics, Toronto, University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Newcomen Centre, Guy's Hospital [London], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Molecular and Cellular Neurobiology, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, 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), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], University of Miami School of Medicine, John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Research Unit on Children's Psychosocial Maladjustment, Université Laval [Québec] (ULaval)-Department of Psychology, University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Manchester Academic Health Sciences Centre, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Autism Genetic Resource Exchange, Autism Speaks, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Psychiatry and Behavioral Sciences, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Social, Genetic and Developmental Psychiatry Centre, Department of Pediatrics, University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Neuropsichiatria Infantile, Ospedale Santa Croce, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, University of Toronto, Child Study Centre, Yale University School of Medicine, University of Oxford [Oxford]-Warneford Hospital, University of Alberta, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Carolina Institute for Developmental Disabilities, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, Physiopathologie des Maladies du Système Nerveux Central, 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), Stanford School of Medicine [Stanford], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Children’s Hospital of Philadelphia (CHOP )-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Yale School of Medicine [New Haven, Connecticut] (YSM), King‘s College London-The Institute of Psychiatry, University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B, University of Oxford, Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Oxford-Warneford Hospital, University of Pennsylvania, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, CNTNAP2, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Nerve Tissue Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Language Development, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, autism spectrum disorders (ASDs), Gene Frequency, Risk Factors, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Allele, GENOME-WIDE ASSOCIATION, Child, Molecular Biology, Allele frequency, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Association Studies Articles, Membrane Proteins, General Medicine, medicine.disease, Genetic architecture, Child Development Disorders, Pervasive, common variant, Perturbações do Desenvolvimento Infantil e Saúde Mental, Autism, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

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

Author

Veronica J. Vieland, Stephen W. Scherer, Elizabeth A. Heron, Barbara Parrini, Jeremy R. Parr, Louise Gallagher, Jeff Munson, Annemarie Poustka, Susan E. Folstein, Irene Drmic, Gudrun Nygren, John P. Rice, Jeff Salt, Simon Wallace, Geraldine Dawson, Daniel H. Geschwind, Annette Estes, Sean Brennan, Alistair T. Pagnamenta, Nancy J. Minshew, Christina Corsello, Jonathan Green, William M. McMahon, Christopher Gillberg, Kathryn Roeder, Lambertus Klei, Anath C. Lionel, Bridget A. Fernandez, Thomas Bourgeron, Ellen M. Wijsman, Gerard D. Schellenberg, Wendy Roberts, Jeremy Goldberg, Frederico Duque, Ghazala Mirza, Sean Ennis, Joana Almeida, Nadine M. Melhem, Jillian P. Casey, Roberta Igliozzi, Ricardo Segurado, Carine Mantoulan, Katy Renshaw, Kai Wang, Andrew D. Paterson, Raffaella Tancredi, Matthew Nicholas Hill, Richard Anney, Christian R. Marshall, Anthony P. Monaco, Linda Lotspeich, Marion Leboyer, Richard Holt, Andrew Pickles, Vlad Kustanovich, William M. Mahoney, Jessica Brian, Inês Sousa, Peter Szatmari, Vanessa Hus, Janine A. Lamb, Hakon Hakonarson, Lonnie Zwaigenbaum, John Tsiantis, David J. Posey, Olena Korvatska, Guillermo Casallo, Rita M. Cantor, Bhooma Thiruvahindrapduram, Nadia Bolshakova, Sven Bölte, Alison K. Merikangas, Brian L. Yaspan, Cecilia Kim, Andrew Crossett, Fritz Poustka, Danielle Zurawiecki, Agatino Battaglia, Sabata C. Lund, Ann P. Thompson, Bennett L. Leventhal, Jessica Rickaby, Zhouzhi Wang, John I. Nurnberger, Astrid M. Vicente, Maretha de Jonge, Tiago R. Magalhaes, Michael L. Cuccaro, Val C. Sheffield, Nuala Sykes, Elena Maestrini, Guiomar Oliveira, Joseph D. Buxbaum, Fred R. Volkmar, Shawn Wood, Magdalena Laskawiec, Katherine Sansom, Herman van Engeland, Jane McGrath, Thomas H. Wassink, Su H. Chu, Elena Bacchelli, Carolyn Noakes, Ann Le Couteur, Catarina Correia, Ohsuke Migita, Bernie Devlin, Hilary Coon, Gillian Baird, Joseph Piven, Tom Berney, Ana Tryfon, Abdul Noor, Patrick Bolton, Latha Soorya, Vera Stoppioni, Stephen J. Guter, Joseph T. Glessner, Michael Gill, Christopher J. McDougle, Anthony J. Bailey, Margaret A. Pericak-Vance, Joachim Hallmayer, Christine M. Freitag, Penny Farrar, Kirsty Wing, Katherine E. Tansey, Bernadette Rogé, Michael Rutter, Christina Strawbridge, Brett S. Abrahams, Kerstin Wittemeyer, Laura J. Bierut, Tara Paton, Emily L. Crawford, Jonathan L. Haines, Alexander Kolevzon, Gillian Hughes, Lili Senman, James S. Sutcliffe, John B. Gilbert, Katerina Papanikolaou, Andrew R. Carson, Lynne E Cochrane, Regina Regan, Judith Miller, Susanne Thomson, Helen McConachie, Daisuke Sato, Richard Delorme, Jiannis Ragoussis, Eric Fombonne, Clara Lajonchere, Judith Conroy, Dalila Pinto, Aparna Prasad, Naisha Shah, Stanley F. Nelson, Sabine M. Klauck, Catalina Betancur, John B. Vincent, Eftichia Duketis, Jennifer L. Howe, Edwin H. Cook, Xiao-Qing Liu, Catherine Lord, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, 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, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry, University of Oxford [Oxford]-Warneford Hospital, Newcomen Centre, Guy's Hospital [London], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Child and Adolescent Mental Health, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Autism Research Unit, University of Toronto-The Hospital for sick children [Toronto] (SickKids), Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Scientific Affairs, Autism Speaks, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, 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 Speech and Hearing Sciences [Washington], University of Washington [Seattle], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario], Manchester Academic Health Sciences Centre, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Medicine, Autism Genetic Resource Exchange, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nathan Kline Institute for Psychiatric Research (NKI), Nathan Kline Institute for Psychiatric Research, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-NYU Child Study Center, Centre d'Etudes et de Recherches en PsychoPathologie, Université Toulouse - Jean Jaurès (UT2J), Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Departments of Psychiatry and Neurology, Department of Psychiatry and Behavioral Sciences, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), Centre for Addiction and Mental Health, Clarke Institute, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Institutes of Neuroscience and Health and Society, Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Carolina Institute for Developmental Disabilities, Social, Genetic and Developmental Psychiatry Centre, Washington University in Saint Louis (WUSTL), Howard Hughes Medical-Institute Carver College of Medicine-University of Iowa [Iowa City], Neuropsichiatria Infantile, Ospedale Santa Croce, Child Study Centre, Yale University School of Medicine, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], University of Alberta, Physiopathologie des Maladies du Système Nerveux Central, 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), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Departments of Biostatistics and Medicine, This research was primarily supported by Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health [HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH057881, MH061009, MH06359, MH066673, MH077930, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261], the Canadian Institutes for Health Research (CIHR), Assistance Publique-Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), GlaxoSmithKline-CIHR Pathfinder Chair (Canada), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health [convention 181 of 19.10.2001], the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Netherlands Organization for Scientific Research [Rubicon 825.06.031], Ontario Ministry of Research and Innovation (Canada), Royal Netherlands Academy of Arts and Sciences [TMF/DA/5801], the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award [075491/Z/04 UK]. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422)., University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), 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), University of Oxford, University of Oxford-Warneford Hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Université de Toulouse (UT)-Université de Toulouse (UT), University of Pennsylvania, Betancur, Catalina, 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
Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genotype, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Databases, Genetic, Copy-number variation, MESH: Genetic Variation, Genetics (clinical), MESH: Databases, Genetic, Genetics, 0303 health sciences, education.field_of_study, MESH: Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH: European Continental Ancestry Group, Autism spectrum disorders, MESH: DNA Copy Number Variations, Genotyping, DNA Copy Number Variations, Genotype, Population, MESH: Autistic Disorder, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Autistic Disorder, SNP association, education, Molecular Biology, Alleles, MESH: Genome, Human, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genome, Human, MESH: Alleles, Haplotype, Genetic Variation, Genetic architecture, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, 030217 neurology & neurosurgery, 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. Author has checked copyright TS 14.06.13 The subscript characters from the abstract have not copied across properly. TS

Published
2010

6. Functional impact of global rare copy number variation in autism spectrum disorders.

Author

Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, 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 A, 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, 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, Pilorge M, Piven J, Ponting CP, 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, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, 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, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, and Betancur C

Subjects
Case-Control Studies, Cell Movement, Child, Child Development Disorders, Pervasive pathology, Cytoprotection, Europe ethnology, Genome-Wide Association Study, Humans, Signal Transduction, Social Behavior, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive physiopathology, DNA Copy Number Variations genetics, Gene Dosage genetics, Genetic Predisposition to Disease genetics
Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Published
2010
Full Text
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7. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.

Author

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, and Hakonarson H

Subjects
Case-Control Studies, Cell Adhesion Molecules, Neuronal genetics, Cohort Studies, Europe ethnology, Gene Regulatory Networks genetics, Genetic Predisposition to Disease genetics, Genotype, Humans, Polymerase Chain Reaction, Polymorphism, Single Nucleotide genetics, Reproducibility of Results, Autistic Disorder genetics, Gene Dosage genetics, Genetic Variation genetics, Genome, Human genetics, Neurons metabolism, Ubiquitin metabolism
Abstract

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

Published
2009
Full Text
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