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      Is Open Access

      Individual common variants exert weak effects on the risk for autism spectrum disorderspi

      research-article
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      Human Molecular Genetics
      Oxford University Press

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          Abstract

          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.

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          Most cited references50

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          De novo gene disruptions in children on the autistic spectrum.

          Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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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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              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
                Hum. Mol. Genet
                hmg
                hmg
                Human Molecular Genetics
                Oxford University Press
                0964-6906
                1460-2083
                1 November 2012
                26 July 2012
                26 July 2012
                : 21
                : 21
                : 4781-4792
                Affiliations
                [1 ]Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College , Dublin 8, Ireland,
                [2 ]Department of Psychiatry, University 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, University of Toronto , Toronto, ON, CanadaM5G 1L7,
                [4 ]Hospital Pediátrico de Coimbra , 3000–076 Coimbra, Portugal,
                [5 ]Department of Biology, University of Bologna , 40126 Bologna, Italy,
                [6 ]Guy's and St Thomas' NHS Trust & King's College, London SE1 9RT, UK,
                [7 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt , 60528 Frankfurt, Germany,
                [8 ]Department of Psychiatry,
                [9 ]MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry , King's College, London SE5 8AF, UK,
                [10 ]Human Genetics and Cognitive Functions, Institut Pasteur and
                [11 ]University Paris Diderot-Paris 7 , CNRS URA 2182 , Fondation FondaMental , 75015 Paris, France,
                [12 ]Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto , Toronto, ON, CanadaM5G 1Z8,
                [13 ]School of Medicine, Medical Science University College , Dublin 4, Ireland,
                [14 ]Instituto Nacional de Saude Dr Ricardo Jorge and Instituto Gulbenkian de Cîencia , 1649-016 Lisbon, Portugal,
                [15 ]BioFIG—Center for Biodiversity, Functional and Integrative Genomics , Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal,
                [16 ]Department of Psychology, University of Michigan , Ann Arbor, MI 48109, USA,
                [17 ]Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience and
                [18 ]Center for Human Genetics Research, Vanderbilt University Medical Centre , Nashville, TN 37232, USA,
                [19 ]Department of Child Psychiatry, University Medical Center , Utrecht, 3508 GA, The Netherlands,
                [20 ]Child and Adolescent Psychiatry, APHP, Hôpital Robert Debré , 75019 Paris, France,
                [21 ]Department of Speech and Hearing Sciences,
                [22 ]Department of Psychiatry and Behavioral Sciences,
                [23 ]Department of Biostatistics and
                [24 ]Department of Medicine, University of Washington , Seattle, WA 98195, USA,
                [25 ]Wellcome Trust Centre for Human Genetics, University of Oxford , Oxford OX3 7BN, UK,
                [26 ]Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, NL, CanadaA1B 3V6,
                [27 ]Department of Psychiatry, University of Miami School of Medicine , Miami, FL 33136, USA,
                [28 ]Division of Psychiatry, McGill University , Montreal, QC, CanadaH3A 1A1,
                [29 ]The John P. Hussman Institute for Human Genomics, University of Miami , Miami, FL 33101, USA,
                [30 ]Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden,
                [31 ]The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia , Philadelphia, PA 19104, USA,
                [32 ]Academic Department of Child Psychiatry, University of Manchester , Manchester M9 7AA, UK,
                [33 ]Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago , Chicago, IL 60608, USA,
                [34 ]The Seaver Autism Center for Research and Treatment, Department of Psychiatry, The Friedman Brain Institute, Mount Sinai School of Medicine , New York NY 10029, USA,
                [35 ]Autism Genetic Resource Exchange, Autism Speaks , Los Angeles, CA 90036-4234, USA,
                [36 ]Centre for Integrated Genomic Medical Research and
                [37 ]Department of Medicine, School of Epidemiology and Health Science, University of Manchester , Manchester M13 9PT, UK,
                [38 ]Department of Psychiatry, Groupe hospitalier Henri Mondor-Albert Chenevier, INSERM U995, AP-HP; University Paris 12, Fondation FondaMental , Créteil 94000, France,
                [39 ]Institutes of Neuroscience and Health and Society, Newcastle University, Newcastle upon Tyne NE1 7RU, UK,
                [40 ]Nathan Kline Institute for Psychiatric Research (NKI) , 140 Old Orangeburg Road, Orangeburg, NY 10962, USA,
                [41 ]Department of Child and Adolescent Psychiatry, New York University, NYU Child Study Center , New York, NY 10016, USA,
                [42 ]Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Manitoba , Winnipeg, MB, Canada,
                [43 ]Center for Autism and the Developing Brain, Weill Cornell Medical College , White Plains, NY, USA,
                [44 ]Department of Psychiatry, Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine , Stanford, CA 94304, USA,
                [45 ]Centre d'Eudes et de Recherches en Psychopathologie, University de Toulouse Le Mirail , Toulouse 31200, France,
                [46 ]Department of Psychiatry, Indiana University School of Medicine , Indianapolis, IN 46202, USA,
                [47 ]Department of Neurology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213, USA
                [48 ]University Department of Child Psychiatry, Athens University , Medical School, Agia Sophia Children's Hospital , 115 27 Athens, Greece,
                [49 ]Stella Maris Institute for Child and Adolescent Neuropsychiatry , 56128 Calambrone (Pisa), Italy,
                [50 ]Department of Statistics, Carnegie Mellon University , Pittsburgh, PA, USA,
                [51 ]Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, University of Iowa , Iowa City, IA 52242, USA,
                [52 ]Neuropsichiatria Infantile, Ospedale Santa Croce, 61032 Fano, Italy,
                [53 ]Department of Psychiatry and Behavioural Neurosciences, McMaster University , Hamilton, ON, CanadaL8N 3Z5,
                [54 ]Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto , Toronto, ON, CanadaM5G 1X8,
                [55 ]Child Study Centre, Yale University , New Haven, CT 06520, USA,
                [56 ]Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht , Utrecht 3584 CX, The Netherlands,
                [57 ]Department of Pediatrics, University of Alberta , Edmonton, AB, CanadaT6G 2J3,
                [58 ]BC Mental Health and Addictions Research Unit, University of British Columbia , Vancouver, BC, CanadaV5Z4H4,
                [59 ]Department of Human Genetics and
                [60 ]Department of Neurology, Los Angeles School of Medicine, University of California , Los Angeles, CA 90095, USA,
                [61 ]Psychiatry Department, University of Utah Medical School , Salt Lake City, UT 84108, USA,
                [62 ]Autism Speaks , New York, NY, USA,
                [63 ]Department of Psychiatry and
                [64 ]Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599-3366, USA,
                [65 ]Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ) , Heidelberg 69120, Germany,
                [66 ]Office of the President, Tufts University , Boston, MA, USA,
                [67 ]Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford, OX3 7JX, UK,
                [68 ]Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA 19104, USA,
                [69 ]Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine , Philadelphia, PA 19104, USA,
                [70 ]Department of Psychiatry, Carver College of Medicine , Iowa City, IA 52242, USA,
                [71 ]INSERM U952 ,
                [72 ]CNRS UMR 7224 and
                [73 ]UPMC Univ Paris 06 , Paris 75005, France and
                [74 ]Battelle Center for Mathematical Medicine, The 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, University of Pittsburgh School of Medicine, 3811 O'Hara St., Pittsburgh, PA 15213. Tel: +1 4122466642; Fax: +1 4122466640; Email: devlinbj@ 123456upmc.edu
                [†]

                Writing Committee.

                [‡]

                Present address: The Seaver Autism Center for Research and Treatment, Department of Psychiatry and The Friedman Brain Institute, Mount Sinai School of Medicine, New York NY 10029, USA.

                [¶]

                Present address: Lurie Center for Autism, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Lexington, MA 0242 USA.

                [§]

                Present address: Center for Autism Research, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

                [∥]

                Lead AGP investigators.

                [#]

                Genotype production.

                Article
                dds301
                10.1093/hmg/dds301
                3471395
                22843504
                fde32573-ad07-4ef2-87f8-c0484cea53a1
                © The Author 2012. 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
                : 22 March 2012
                : 13 July 2012
                : 19 July 2012
                Page count
                Pages: 12
                Categories
                Association Studies Articles

                Genetics
                Genetics

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