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Cell. 2020 Feb 6;180(3):568-584.e23. doi: 10.1016/j.cell.2019.12.036. Epub 2020 Jan 23.

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Collaborators (149)

Aleksic B, Anney R, Barbosa M, Bishop S, Brusco A, Bybjerg-Grauholm J, Carracedo A, Chan MCY, Chiocchetti AG, Chung BHY, Coon H, Cuccaro ML, Curró A, Dalla Bernardina B, Doan R, Domenici E, Dong S, Fallerini C, Fernández-Prieto M, Ferrero GB, Freitag CM, Fromer M, Gargus JJ, Geschwind D, Giorgio E, González-Peñas J, Guter S, Halpern D, Hansen-Kiss E, He X, Herman GE, Hertz-Picciotto I, Hougaard DM, Hultman CM, Ionita-Laza I, Jacob S, Jamison J, Jugessur A, Kaartinen M, Knudsen GP, Kolevzon A, Kushima I, Lee SL, Lehtimäki T, Lim ET, Lintas C, Lipkin WI, Lopergolo D, Lopes F, Ludena Y, Maciel P, Magnus P, Mahjani B, Maltman N, Manoach DS, Meiri G, Menashe I, Miller J, Minshew N, Montenegro EMS, Moreira D, Morrow EM, Mors O, Mortensen PB, Mosconi M, Muglia P, Neale BM, Nordentoft M, Ozaki N, Palotie A, Parellada M, Passos-Bueno MR, Pericak-Vance M, Persico AM, Pessah I, Puura K, Reichenberg A, Renieri A, Riberi E, Robinson EB, Samocha KE, Sandin S, Santangelo SL, Schellenberg G, Scherer SW, Schlitt S, Schmidt R, Schmitt L, Silva IMW, Singh T, Siper PM, Smith M, Soares G, Stoltenberg C, Suren P, Susser E, Sweeney J, Szatmari P, Tang L, Tassone F, Teufel K, Trabetti E, Trelles MDP, Walsh CA, Weiss LA, Werge T, Werling DM, Wigdor EM, Wilkinson E, Willsey AJ, Yu TW, Yu MHC, Yuen R, Zachi E, Agerbo E, Als TD, Appadurai V, Bækvad-Hansen M, Belliveau R, Buil A, Carey CE, Cerrato F, Chambert K, Churchhouse C, Dalsgaard S, Demontis D, Dumont A, Goldstein J, Hansen CS, Hauberg ME, Hollegaard MV, Howrigan DP, Huang H, Maller J, Martin AR, Martin J, Mattheisen M, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Schork AJ, Thompson WK, Turley P, Walters RK.

Author information

1
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
2
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
3
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA.
4
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea.
6
Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
7
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
8
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
9
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
10
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
12
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
13
Computer Engineering Department, Bilkent University, Ankara, Turkey.
14
Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
15
Center for Autism Research and Translation, University of California, Irvine, Irvine, CA, USA.
16
MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA, USA.
17
Division of Genetics, Boston Children's Hospital, Boston, MA, USA; Division of Developmental Medicine, Boston Children's Hospital, Boston, MA, USA.
18
Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France.
19
Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
20
Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
21
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA; Department of Molecular Physiology and Biophysics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
22
National Institute of Mental Health, NIH, Bethesda, MD, USA.
23
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
24
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
25
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA; Computer Engineering Department, Bilkent University, Ankara, Turkey.
26
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address: stephan.sanders@ucsf.edu.
27
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA. Electronic address: roeder@andrew.cmu.edu.
28
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. Electronic address: mjdaly@broadinstitute.org.
29
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: joseph.buxbaum@mssm.edu.

Abstract

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

KEYWORDS:

autism spectrum disorder; cell type; cytoskeleton; excitatory neurons; excitatory-inhibitory balance; exome sequencing; genetics; inhibitory neurons; liability; neurodevelopment

PMID:
31981491
DOI:
10.1016/j.cell.2019.12.036

Conflict of interest statement

Declaration of Interests B.M.N. is a member of the scientific advisory board at Deep Genomics and consults for Biogen, Camp4 Therapeutics Corporation, Takeda Pharmaceutical, and Biogen. During the last 3 years, C.M. Freitag has been consultant to Desitin and Roche and receives royalties for books on ASD, ADHD, and MDD.

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