Scientific Understanding of Consciousness
Genes Disrupted in Autism
Nature 515, 209–215 (13 November 2014)
Synaptic, transcriptional and chromatin genes disrupted in autism
Silvia De Rubeis, et.al.
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York 10029, New York, USA.
Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Medical Center Freiburg; Center for Mental Disorders, 79106 Freiburg, Germany.
Department of Child Psychiatry & SGDP Centre, King’s College London Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Department of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Genomic Medicine Group, CIBERER, University of Santiago de Compostela and Galician Foundation of Genomic Medicine (SERGAS), 15706 Santiago de Compostela, Spain.
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.
Harvard Medical School, Boston, Massachusetts 02115, USA.
Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA.
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.
Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
Department of Psychiatry, University of Utah, Salt Lake City, Utah 84108, USA.
Duke Institute for Brain Sciences, Duke University, Durham, North Carolina 27708, USA.
Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s, Newfoundland A1B 3V6, Canada.
Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.
University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania 19104, USA.
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60608, USA.
Department of Biostatistics, Columbia University, New York, New York 10032, USA.
Hospital Nacional de Niños Dr Saenz Herrera, CCSS, Child Developmental and Behavioral Unit, San José, Costa Rica.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Institute of Child Health, University College London, London, WC1N 1EH, UK.
Department of Clinical Chemistry, Fimlab Laboratories, SF-33100 Tampere, Finland.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Department of Psychiatry Kaiser Permanente, San Francisco, California 94118, USA.
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
MRC Centre for Neuropsychiatric Genetics and Genomics, and the Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, CF24 4HQ, UK.
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Universidad Complutense, 28040 Madrid, Spain.
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Department of Child Psychiatry, University of Tampere and Tampere University Hospital, 33521 Tampere, Finland SF-33101.
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143–0984, USA.
Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Translational Brain Medicine in Psychiatry and Neurology, University Hospital RWTH Aachen / JARA Brain Translational Medicine, 52056 Aachen, Germany.
Department of Child and Adolescent Mental Health, Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, WC1N 3JH, UK.
Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
Department of Child and Adolescent Psychiatry, Saarland University Hospital, D-66424 Homburg, Germany.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-9663, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Institute for Molecular Medicine Finland, University of Helsinki, FI-00014 Helsinki, Finland.
Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
McLaughlin Centre, University of Toronto, Toronto, Ontario M5S 1A1, Canada.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Lists of participants appear in the Supplementary Information.
The DDD Study
Homozygosity Mapping Collaborative for Autism
The Autism Sequencing Consortium
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability–transcription coupling, as well as histone-modifying enzymes and chromatin remodellers—most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Features of subjects with autism spectrum disorder (ASD) include compromised social communication and interaction. Because the bulk of risk arises from de novo and inherited genetic variation, characterizing which genes are involved informs ASD neurobiology and reveals part of what makes us social beings.
Whole-exome sequencing (WES) studies have proved fruitful in uncovering risk-conferring variation, especially by enumerating de novo variation, which is sufficiently rare that recurrent mutations in a gene provide strong evidence for a causal link to ASD. De novo loss-of-function (LoF) single-nucleotide variants (SNVs) or insertion/deletion (indel) variants are found in 6.7% more ASD subjects than in matched controls and implicate nine genes from the first 1,000 ASD subjects analysed. Moreover, because there are hundreds of genes involved in ASD risk, ongoing WES studies should identify additional ASD genes as an almost linear function of increasing sample size.
Here we conduct the largest ASD WES study so far, analysing 16 sample sets comprising 15,480 DNA samples. Unlike earlier WES studies, we do not rely solely on counting de novo LoF variants, rather we use novel statistical methods to assess association for autosomal genes by integrating de novo, inherited and case-control LoF counts, as well as de novo missense variants predicted to be damaging. For many samples original data from sequencing performed on Illumina HiSeq 2000 systems were used to call SNVs and indels in a single large batch using GATK (v2.6). De novo mutations were called using enhancements of earlier methods, with calls validating at extremely high rates.
We adopted TADA (transmission and de novo association), a weighted, statistical model integrating de novo, transmitted and case-control variation. TADA uses a Bayesian gene-based likelihood model including per-gene mutation rates, allele frequencies, and relative risks of particular classes of sequence changes.
Three critical pathways for typical development are damaged by risk variation: chromatin remodelling, transcription and splicing, and synaptic function. Chromatin remodelling controls events underlying the formation of neural connections, including neurogenesis and neural differentiation, and relies on epigenetic marks as post-translational modifications of histones. Here we provide extensive evidence for HMGs and readers in sporadic ASD, implicating specifically lysine methylation and extending the mutational landscape of the emergent ASD gene CHD8 to missense variants. Splicing is implicated by the enrichment of RBFOX targets in the top ASD candidates. Risk variation also affects multiple classes and components of synaptic networks, from receptors and ion channels to scaffolding proteins. Because a wide set of synaptic genes is disrupted in idiopathic ASD, it seems reasonable to suggest that altered chromatin dynamics and transcription, induced by disruption of relevant genes, leads to impaired synaptic function as well. De novo mutations in ASD, intellectual disability and schizophrenia cluster to synaptic genes, and synaptic defects have been reported in models of these disorders. Integrity of synaptic function is essential for neural physiology, and its perturbation could represent the intersection between diverse neuropsychiatric disorders.
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