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

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      Human Molecular Genetics
      Oxford University Press

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          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.

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Advances in autism genetics: on the threshold of a new neurobiology.

            Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.
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              Association between microdeletion and microduplication at 16p11.2 and autism.

              Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
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                Author and article information

                Journal
                Hum Mol Genet
                hmg
                hmg
                Human Molecular Genetics
                Oxford University Press
                0964-6906
                1460-2083
                15 October 2010
                27 July 2010
                27 July 2010
                : 19
                : 20
                : 4072-4082
                Affiliations
                [1 ]Autism Genetics Group, Department of Psychiatry, School of Medicine, simpleTrinity College , Dublin 8, Ireland,
                [2 ]Department of Psychiatry, simpleUniversity of Pittsburgh School of Medicine , Pittsburgh, PA 15232, USA,
                [3 ]The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children and Department of Molecular Genetics, simpleUniversity of Toronto , ONM5G 1L7, Canada,
                [4 ]School of Medicine andsimpleMedical Science University College , Dublin 4, Ireland,
                [5 ]simpleInstituto Nacional de Saude Dr Ricardo Jorge and Instituto Gulbenkian de Cîencia , 1649-016 Lisbon, Portugal,
                [6 ]BioFIG—Center for Biodiversity, Functional & Integrative Genomics, Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal,
                [7 ]Department of Neurology, simpleUniversity of California at Los Angeles, School of Medicine , Los Angeles, CA 90095, USA,
                [8 ]Wellcome Trust Centre for Human Genetics, simpleUniversity of Oxford , Oxford OX3 7BN, UK,
                [9 ]Hospital Pediátrico de Coimbra, 3000–076, Coimbra, Portugal,
                [10 ]Department of Biology, simpleUniversity of Bologna , 40126 Bologna, Italy,
                [11 ]Department of Psychiatry, simpleUniversity of Oxford , Warneford Hospital, Headington, Oxford OX3 7JX, UK,
                [12 ]simpleNewcomen Centre, Guy's Hospital , London SE1 9RT, UK,
                [13 ]Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy,
                [14 ]Child and Adolescent Mental Health, simpleUniversity of Newcastle, Sir James Spence Institute , Newcastle Upon Tyne NE1 4LP, UK,
                [15 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, simpleJ.W. Goethe University Frankfurt , 60528 Frankfurt, Germany,
                [16 ]Department of Child and Adolescent Psychiatry, simpleInstitute of Psychiatry , London SE5 8AF, UK,
                [17 ]Human Genetics and Cognitive Functions, Institut Pasteur, simpleUniversity Paris Diderot-Paris 7 , CNRS URA 2182, Fondation FondaMental, 75015 Paris, France,
                [18 ]Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, simpleUniversity of Toronto , Toronto, ONM5G 1Z8, Canada,
                [19 ]Autism and Communicative Disorders Centre, simpleUniversity of Michigan , Ann Arbor, MI 48109, USA,
                [20 ]Department of Statistics, simpleCarnegie Mellon University , Pittsburgh, PA, USA,
                [21 ]Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, simpleVanderbilt University , Nashville, TN 37232, USA,
                [22 ]Autism Speaks, New York, NY 10016, USA,
                [23 ]Department of Psychiatry, simpleUniversity of North Carolina , Chapel Hill, NC 27599, USA,
                [24 ]Department of Child Psychiatry, simpleUniversity Medical Center , Utrecht 3508 GA, The Netherlands,
                [25 ]APHP, Hôpital Robert Debré, simpleChild and Adolescent Psychiatry , 75019 Paris, France,
                [26 ]Department of Speech and Hearing Sciences,
                [27 ]Department of Medicine,
                [28 ]Department of Psychiatry and Behavioral Sciences,
                [29 ]Department of Biostatistics and
                [30 ]Department of Medicine, simpleUniversity of Washington , Seattle, WA 98195, USA,
                [31 ]Disciplines of Genetics and Medicine, simpleMemorial University of Newfoundland , St John's, NL A1B 3V6, Canada,
                [32 ]The John P. Hussman Institute for Human Genomics, simpleUniversity of Miami , Miami, FL 33101, USA,
                [33 ]Division of Psychiatry, simpleMcGill University , Montreal, QCH3A 1A1, Canada,
                [34 ]Department of Child and Adolescent Psychiatry, simpleGöteborg University Göteborg , Göteborg S41345, Sweden,
                [35 ]The Center for Applied Genomics, Division of Human Genetics, simpleThe Children's Hospital of Philadelphia , Philadelphia, PA 19104, USA,
                [36 ]Department of Psychiatry and Behavioural Neurosciences, simpleMcMaster University , Hamilton, ONL8N 3Z5, Canada,
                [37 ]Academic Department of Child Psychiatry, simpleBooth Hall of Children's Hospital , Blackley, Manchester M9 7AA, UK,
                [38 ]Institute for Juvenile Research, Department of Psychiatry, simpleUniversity of Illinois at Chicago , Chicago, IL 60608, USA,
                [39 ]Department of Pediatrics, Children's Hospital of Philadelphia, simpleUniversity of Pennsylvania School of Medicine , Philadelphia, PA 19104, USA,
                [40 ]Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,
                [41 ]The Seaver Autism Center for Research and Treatment, Department of Psychiatry, simpleMount Sinai School of Medicine , New York 10029, USA,
                [42 ]simpleAutism Genetic Resource Exchange, Autism Speaks , Los Angeles, CA 90036-4234, USA,
                [43 ]Centre for Integrated Genomic Medical Research, simpleUniversity of Manchester , Manchester M13 9PT, UK,
                [44 ]INSERM U995, Department of Psychiatry, Groupe hospitalier Henri Mondor-Albert Chenevier, AP-HP, simpleUniversity Paris 12, Fondation FondaMental , Créteil 94000, France,
                [45 ]Nathan Kline Institute for Psychiatric Research (NKI), 140 Old Orangeburg Road, Orangeburg, NY 10962, USA,
                [46 ]Department of Child and Adolescent Psychiatry, simpleNew York University and NYU Child Study Center , 550 First Avenue, New York, NY 10016, USA,
                [47 ]Department of Psychiatry, Division of Child and Adolescent Psychiatry and Child Development, simpleStanford University School of Medicine , Stanford, CA 94304, USA,
                [48 ]Department of Pediatrics, simpleMcMaster University , Hamilton, ON L8N 3Z5, Canada,
                [49 ]Department of Psychiatry, simpleIndiana University School of Medicine , Indianapolis, IN 46202, USA,
                [50 ]Psychiatry Department, simpleUniversity of Utah Medical School , Salt Lake City, UT 84108, USA,
                [51 ]Department of Psychiatry and
                [52 ]Department of Neurology, simpleUniversity of Pittsburgh School of Medicine , Pittsburgh, PA 15213, USA,
                [53 ]Department of Human Genetics, simpleUniversity of California at Los Angeles School of Medicine , Los Angeles, CA 90095, USA,
                [54 ]Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, simpleUniversity of Toronto , Toronto, ONM5G 1X8, Canada,
                [55 ]University Department of Child Psychiatry, simpleAthens University , Medical School, Agia Sophia Children's Hospital, 115 27 Athens, Greece,
                [56 ]Institutes of Neuroscience and Health and Society, simpleNewcastle University , Newcastle Upon Tyne NE1 7RU, UK,
                [57 ]Department of Medicine, School of Epidemiology and Health Science, simpleUniversity of Manchester , Manchester M13 9PT, UK,
                [58 ]Carolina Institute for Developmental Disabilities, simpleUniversity of North Carolina at Chapel Hill , Chapel Hill, NC 27599-3366, USA,
                [59 ]Centre d'Eudes et de Recherches en Psychopathologie, simpleUniversity de Toulouse Le Mirail , Toulouse 31200, France,
                [60 ]Social, Genetic and Developmental Psychiatry Centre, simpleInstitute of Psychiatry , London SE5 8AF, UK,
                [61 ]Department of Psychiatry, simpleWashington University in St Louis, School of Medicine , St Louis, MO 63130, USA,
                [62 ]Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, simpleUniversity of Iowa , Iowa City, IA 52242, USA,
                [63 ]Neuropsichiatria Infantile, simpleOspedale Santa Croce , 61032 Fano, Italy,
                [64 ]Child Study Centre, simpleYale University , New Haven, CT 06520, USA,
                [65 ]Department of Psychiatry, simpleCarver College of Medicine , Iowa City, IA 52242, USA,
                [66 ]Department of Pediatrics, simpleUniversity of Alberta , Edmonton, AL T6G 2J3, Canada,
                [67 ]INSERM U952 and CNRS UMR 7224 and UPMC Univ Paris 06, Paris 75005, France,
                [68 ]Center for Human Genetics Research, simpleVanderbilt University Medical Centre , Nashville, TN 37232, USA,
                [69 ]Pathology and Laboratory Medicine, simpleUniversity of Pennsylvania , Philadelphia, PA 19104, USA and
                [70 ]Battelle Center for Mathematical Medicine, simpleThe Research Institute at Nationwide Children's Hospital and The Ohio State University , Columbus, OH 43205, USA
                Author notes
                [* ]To whom correspondence should be addressed at: Department of Psychiatry, simpleUniversity of Pittsburgh School of Medicine , 3811 O'Hara St, Pittsburgh, PA 15213, USA. Tel: +1 4122466642; Fax: +1 4122466640; Email: devlinbj@ 123456upmc.edu
                [†]

                Lead AGP investigators who contributed equally to this project.

                [‡]

                Deceased.

                Article
                ddq307
                10.1093/hmg/ddq307
                2947401
                20663923
                5beef692-c1c0-470a-97a0-a128e10b73a2
                © The Author 2010. Published by Oxford University Press

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 April 2010
                : 2 July 2010
                : 16 July 2010
                Categories
                Association Studies Articles

                Genetics
                Genetics

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