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

机译：对影响自闭症风险的常见等位基因进行全基因组扫描

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摘要

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.
机译：尽管自闭症谱系障碍（ASD）具有重要的遗传基础，但大多数已知的遗传风险都可追溯到稀有变异体，主要是拷贝数变异体（CNV）。为了确定常见的风险差异，自闭症基因组计划（AGP）协会对1558个基因型进行了严格定义，以定义100万个单核苷酸多态性（SNP）的ASD家族，并分析了这些SNP基因型与ASD的关联。在四个主要关联分析之一中，位于MACROD2中的标记rs4141463的关联信号超过了全基因组关联显着性阈值P <5×10 -8 。当分析较小的复制样本时，rs4141463的风险等位基因再次被过度传播；然而，根据获胜者的诅咒，复制样本中的效应量要小得多。对于合并的样本，关联信号几乎不低于P <5×10 -8 阈值。对表型亚型的探索性分析在多次测试校正后未产生显着关联。但是，它们确实在几个基因（KIAA0564，PLD5，POU6F2，ST8SIA2和TAF1C）内产生强信号。

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  • 来源
    《Human Molecular Genetics》 |2010年第20期|p.4072-4082|共11页
  • 作者

    Richard Anney; Lambertus Klei; Dalila Pinto; Regina Regan; Judith Conroy; Tiago R. Magalhaes; Catarina Correia; Brett S. Abrahams; Nuala Sykes; Alistair T. Pagnamenta; Joana Almeida; Elena Bacchelli; Anthony J. Bailey; Gillian Baird; Agatino Battaglia; Tom Berney; Nadia Bolshakova; Sven Bölte;

  • 作者单位

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA,;

    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, ON M5G 1L7, Canada,;

    School of Medicine and Medical Science University College, Dublin 4, Ireland,;

    School of Medicine and Medical Science University College, Dublin 4, Ireland,;

    Instituto Nacional de Saude Dr Ricardo Jorge and Instituto Gulbenkian de Cîencia, 1649-016 Lisbon, Portugal,|BioFIG—Center for Biodiversity, Functional & Integrative Genomics, Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal,;

    Instituto Nacional de Saude Dr Ricardo Jorge and Instituto Gulbenkian de Cîencia, 1649-016 Lisbon, Portugal,|BioFIG—Center for Biodiversity, Functional & Integrative Genomics, Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal,;

    Department of Neurology, University of California at Los Angeles, School of Medicine, Los Angeles, CA 90095, USA,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Hospital Pediátrico de Coimbra, 3000–076, Coimbra, Portugal,;

    Department of Biology, University of Bologna, 40126 Bologna, Italy,;

    Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK,;

    Newcomen Centre, Guy's Hospital, London SE1 9RT, UK,;

    Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy,;

    Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle Upon Tyne NE1 4LP, UK,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany,;

    Department of Child and Adolescent Psychiatry, Institute of Psychiatry, London SE5 8AF, UK,;

    Human Genetics and Cognitive Functions, Institut Pasteur, University Paris Diderot-Paris 7, CNRS URA 2182, Fondation FondaMental, 75015 Paris, France,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, ON M5G 1Z8, Canada,;

    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, ON M5G 1L7, Canada,;

    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, ON M5G 1L7, Canada,;

    School of Medicine and Medical Science University College, Dublin 4, Ireland,;

    Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, MI 48109, USA,;

    Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA,;

    Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA,;

    Autism Speaks, New York, NY 10016, USA,|Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA,;

    Department of Child Psychiatry, University Medical Center, Utrecht 3508 GA, The Netherlands,;

    APHP, Hôpital Robert Debré, Child and Adolescent Psychiatry, 75019 Paris, France,;

    Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, ON M5G 1Z8, Canada,;

    Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany,;

    Hospital Pediátrico de Coimbra, 3000–076, Coimbra, Portugal,;

    Department of Speech and Hearing Sciences,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, NL A1B 3V6, Canada,;

    The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA,;

    Division of Psychiatry, McGill University, Montreal, QC H3A 1A1, Canada,;

    Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany,;

    The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA,;

    Department of Child and Adolescent Psychiatry, Göteborg University Göteborg, Göteborg S41345, Sweden,;

    The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA,;

    Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5, Canada,;

    Academic Department of Child Psychiatry, Booth Hall of Children's Hospital, Blackley, Manchester M9 7AA, UK,;

    Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA,;

    The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA,|Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    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, ON M5G 1L7, Canada,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, MI 48109, USA,;

    Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy,;

    The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA,;

    Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,;

    The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA,;

    Department of Medicine,;

    Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, CA 90036-4234, USA,;

    Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, CA 90036-4234, USA,;

    Centre for Integrated Genomic Medical Research, University of Manchester, Manchester M13 9PT, UK,;

    Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK,;

    INSERM U995, Department of Psychiatry, Groupe hospitalier Henri Mondor-Albert Chenevier, AP-HP, University Paris 12, Fondation FondaMental, Créteil 94000, France,;

    Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle Upon Tyne NE1 4LP, UK,;

    Nathan Kline Institute for Psychiatric Research (NKI), 140 Old Orangeburg Road, Orangeburg, NY 10962, USA,|Department of Child and Adolescent Psychiatry, New York University and NYU Child Study Center, 550 First Avenue, New York, NY 10016, USA,;

    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, ON M5G 1L7, Canada,;

    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, ON M5G 1L7, Canada,;

    Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, MI 48109, USA,;

    Department of Psychiatry, Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, CA 94304, USA,;

    Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA,;

    Department of Biology, University of Bologna, 40126 Bologna, Italy,;

    Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5, Canada,;

    Centre d'Eudes et de Recherches en Psychopathologie, University de Toulouse Le Mirail, Toulouse 31200, France,;

    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, ON M5G 1L7, Canada,;

    Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle Upon Tyne NE1 4LP, UK,;

    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Psychiatry Department, University of Utah Medical School, Salt Lake City, UT 84108, USA,;

    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    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, ON M5G 1L7, Canada,;

    Department of Psychiatry and|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Department of Psychiatry and Behavioral Sciences,;

    Department of Human Genetics, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095, USA,;

    Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, ON M5G 1Z8, Canada,;

    Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto, Toronto, ON M5G 1X8, Canada,;

    Department of Child and Adolescent Psychiatry, Göteborg University Göteborg, Göteborg S41345, Sweden,;

    Hospital Pediátrico de Coimbra, 3000–076, Coimbra, Portugal,;

    University Department of Child Psychiatry, Athens University, Medical School, Agia Sophia Children's Hospital, 115 27 Athens, Greece,;

    Institutes of Neuroscience and Health and Society, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK,;

    Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy,;

    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, ON M5G 1L7, Canada,;

    Department of Medicine, School of Epidemiology and Health Science, University of Manchester, Manchester M13 9PT, UK,;

    Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3366, USA,;

    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA,;

    Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,;

    Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany,;

    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, ON M5G 1L7, Canada,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK,;

    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, ON M5G 1L7, Canada,;

    Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, ON M5G 1Z8, Canada,;

    Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA,;

    Centre d'Eudes et de Recherches en Psychopathologie, University de Toulouse Le Mirail, Toulouse 31200, France,;

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London SE5 8AF, UK,;

    Department of Psychiatry, Washington University in St Louis, School of Medicine, St Louis, MO 63130, USA,;

    Department of Psychiatry, Washington University in St Louis, School of Medicine, St Louis, MO 63130, USA,;

    Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA,;

    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, ON M5G 1L7, Canada,;

    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, ON M5G 1L7, Canada,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, ON M5G 1Z8, Canada,;

    School of Medicine and Medical Science University College, Dublin 4, Ireland,;

    Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA,;

    The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Neuropsichiatria Infantile, Ospedale Santa Croce, 61032 Fano, Italy,;

    Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5, Canada,;

    Stella Maris Institute for Child and Adolescent Neuropsychiatry, 56128 Calambrone (Pisa), Italy,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    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, ON M5G 1L7, Canada,;

    Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5, Canada,;

    Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA,;

    The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA,;

    University Department of Child Psychiatry, Athens University, Medical School, Agia Sophia Children's Hospital, 115 27 Athens, Greece,;

    Department of Child Psychiatry, University Medical Center, Utrecht 3508 GA, The Netherlands,;

    Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto, Toronto, ON M5G 1X8, Canada,;

    Child Study Centre, Yale University, New Haven, CT 06520, USA,;

    Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK,;

    The Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA,;

    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, ON M5G 1L7, Canada,;

    Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242, USA,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Centre d'Eudes et de Recherches en Psychopathologie, University de Toulouse Le Mirail, Toulouse 31200, France,;

    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA,;

    Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA,;

    The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA,;

    Department of Pediatrics, University of Alberta, Edmonton, AL T6G 2J3, Canada,;

    INSERM U952 and CNRS UMR 7224 and UPMC Univ Paris 06, Paris 75005, France,;

    The Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York 10029, USA,;

    Department of Human Genetics, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095, USA,;

    Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, USA,;

    Psychiatry Department, University of Utah Medical School, Salt Lake City, UT 84108, USA,;

    The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Department of Neurology, University of California at Los Angeles, School of Medicine, Los Angeles, CA 90095, USA,;

    Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland,;

    Center for Human Genetics Research, Vanderbilt University Medical Centre, Nashville, TN 37232, USA,;

    Psychiatry Department, University of Utah Medical School, Salt Lake City, UT 84108, USA,;

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK,;

    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA,;

    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, ON M5G 1L7, Canada,;

    The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33101, USA,;

    Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA and;

    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, ON M5G 1L7, Canada,;

    Department of Molecular Physiology and Biophysics, Vanderbilt Kennedy Center, and Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA,;

    Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8N 3Z5, Canada,;

    Instituto Nacional de Saude Dr Ricardo Jorge and Instituto Gulbenkian de Cîencia, 1649-016 Lisbon, Portugal,|BioFIG—Center for Biodiversity, Functional & Integrative Genomics, Campus da FCUL, C2.2.12, Campo Grande, 1749-016 Lisboa, Portugal,;

    Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, OH 43205, USA;

    Department of Biostatistics and|Department of Medicine, University of Washington, Seattle, WA 98195, USA,;

    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA,;

    School of Medicine and Medical Science University College, Dublin 4, Ireland,;

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