title: Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
abstract: Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: stephan.sanders@ucsf.edu.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Computer Engineering, Bilkent University, Ankara, 0680, Turkey.
authors.forename: A Ercument
authors.initials: AE
authors.lastname: Cicek
authors.affiliation: Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Murtha
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Vanessa H
authors.initials: VH
authors.lastname: Bal
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Somer L
authors.initials: SL
authors.lastname: Bishop
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Dong
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Goldberg
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Cai
authors.initials: C
authors.lastname: Jinlu
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Mandell
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreno-De-Luca
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Poultney
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Elise B
authors.initials: EB
authors.lastname: Robinson
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Louw
authors.initials: L
authors.lastname: Smith
authors.affiliation: TheLab, Inc., Los Angeles, CA 90068, USA.
authors.forename: Tor
authors.initials: T
authors.lastname: Solli-Nowlan
authors.affiliation: Program in Biophysics, Harvard University, Boston, MA 02115, USA.
authors.forename: Mack Y
authors.initials: MY
authors.lastname: Su
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Teran
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walker
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Werling
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, T617, Houston, TX 77030, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Departments of Human Genetics and Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095-7088, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: Department of Psychiatry and Institute for Development and disability, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Fombonne
authors.affiliation: Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Grice
authors.affiliation: Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, NY 10605, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lord
authors.affiliation: Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.affiliation: Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.affiliation: Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry and Department of Psychiatry and Human Behavior, Brown University, 70 Ship Street, Box G-E4, Providence, RI 02912, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Morrow
authors.affiliation: Center for Human Genetic Research, Departments of Neurology, Psychiatry, and Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Department of Molecular Physiology & Biophysics, 6133 MRB III, Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Howard Hughes Medical Institute and Division of Genetics and Genomics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Howard Hughes Medical Institute and Division of Genetics and Genomics, Children's Hospital Boston, and Neurology and Pediatrics, Harvard Medical School Center for Life Sciences, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Autism & Developmental Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: Autism & Developmental Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
authors.forename: Christa Lese
authors.initials: CL
authors.lastname: Martin
authors.affiliation: Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, Room 155, Chicago, IL 60637 USA.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.affiliation: Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D060066:Protein Interaction Maps / Q000235:genetics*