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

Anno:

2020

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

Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C Y Chan, Andreas G Chiocchetti, Brian H Y Chung, Hilary Coon, Michael L Cuccaro, Aurora Curró, Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M Freitag, Menachem Fromer, J Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier González-Peñas, Stephen Guter, Danielle Halpern, Emily Hansen-Kiss, Xin He, Gail E Herman, Irva Hertz-Picciotto, David M Hougaard, Christina M Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtimäki, Elaine T Lim, Carla Lintas, W Ian Lipkin, Diego Lopergolo, Fátima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M S Montenegro, Danielle Moreira, Eric M Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B Robinson, Kaitlin E Samocha, Sven Sandin, Susan L Santangelo, Gerry Schellenberg, Stephen W Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M W Silva, Tarjinder Singh, Paige M Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pål Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria Del Pilar Trelles, Christopher A Walsh, Lauren A Weiss, Thomas Werge, Donna M Werling, Emilie M Wigdor, Emma Wilkinson, A Jeremy Willsey, Timothy W Yu, Mullin H C Yu, Ryan Yuen, Elaine Zachi, Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S Hansen, Mads Engel Hauberg, Mads V Hollegaard, Daniel P Howrigan, Hailiang Huang, Julian Maller, Alicia R Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J Schork, Wesley K Thompson, Patrick Turley, Raymond K Walters

Affiliations

1Stanley 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.

2Stanley 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.

3Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA.

4Seaver 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.

5Department 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.

6Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.

7The 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.

8Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

9Stanley 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.

10Seaver 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.

11Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

12Department 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.

13Computer Engineering Department, Bilkent University, Ankara, Turkey.

14Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

15Center for Autism Research and Translation, University of California, Irvine, Irvine, CA, USA.

16MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA, USA.

17Division of Genetics, Boston Children's Hospital, Boston, MA, USA; Division of Developmental Medicine, Boston Children's Hospital, Boston, MA, USA.

18Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France.

19Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.

20Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.

21Vanderbilt 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.

22National Institute of Mental Health, NIH, Bethesda, MD, USA.

23Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

24The 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.

25Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA; Computer Engineering Department, Bilkent University, Ankara, Turkey.

26Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address: stephan.sanders@ucsf.edu.

27Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA; Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA. Electronic address: roeder@andrew.cmu.edu.

28Stanley 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.

29Seaver 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.

PMID: 31981491 PMCID: PMC7250485 DOI: 10.1016/j.cell.2019.12.036

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.