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Neuron. 2015 Sep 23;87(6):1215-33. doi: 10.1016/j.neuron.2015.09.016.

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.

Author information

1
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: stephan.sanders@ucsf.edu.
2
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
3
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Neurosurgery, Program on Neurogenetics, Yale University School of Medicine, New Haven, CT 06520, USA.
5
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.
6
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Computer Engineering, Bilkent University, Ankara, 0680, Turkey.
7
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.
8
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.
9
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
10
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
11
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
12
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.
13
TheLab, Inc., Los Angeles, CA 90068, USA.
14
Program in Biophysics, Harvard University, Boston, MA 02115, USA.
15
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
16
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, T617, Houston, TX 77030, USA.
17
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.
18
Department of Psychiatry and Institute for Development and disability, Oregon Health & Science University, Portland, OR 97239, USA.
19
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.
20
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
21
Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, NY 10605, USA.
22
Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT 06520, USA.
23
Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
24
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.
25
Center for Human Genetic Research, Departments of Neurology, Psychiatry, and Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
26
Department of Molecular Physiology & Biophysics, 6133 MRB III, Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN 37232, USA.
27
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.
28
Autism & Developmental Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
29
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Road, Room 155, Chicago, IL 60637 USA.
30
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
31
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.

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).

PMID:
26402605
PMCID:
PMC4624267
DOI:
10.1016/j.neuron.2015.09.016
[Indexed for MEDLINE]
Free PMC Article
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