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

F Kyle Satterstrom; Jack A Kosmicki; Jiebiao Wang; Michael S Breen; Silvia De Rubeis; Joon-Yong An; Minshi Peng; Ryan Collins; Jakob Grove; Lambertus Klei; Christine Stevens; Jennifer Reichert; Maureen S Mulhern; Mykyta Artomov; Sherif Gerges; Brooke Sheppard; Xinyi Xu; Aparna Bhaduri; Utku Norman; Harrison Brand; Grace Schwartz; Rachel Nguyen; Elizabeth E Guerrero; Caroline Dias; Autism Sequencing Consortium; iPSYCH-Broad Consortium; Catalina Betancur; Edwin H Cook; Louise Gallagher; Michael Gill; James S Sutcliffe; Audrey Thurm; Michael E Zwick; Anders D Børglum; Matthew W State; A Ercument Cicek; Michael E Talkowski; David J Cutler; Bernie Devlin; Stephan J Sanders; Kathryn Roeder; Mark J Daly; Joseph D Buxbaum

doi:10.1016/j.cell.2019.12.036

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

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

Authors

F Kyle Satterstrom¹, Jack A Kosmicki², Jiebiao Wang³, Michael S Breen⁴, Silvia De Rubeis⁴, Joon-Yong An⁵, Minshi Peng³, Ryan Collins⁶, Jakob Grove⁷, Lambertus Klei⁸, Christine Stevens⁹, Jennifer Reichert¹⁰, Maureen S Mulhern¹⁰, Mykyta Artomov⁹, Sherif Gerges⁹, Brooke Sheppard¹¹, Xinyi Xu¹⁰, Aparna Bhaduri¹², Utku Norman¹³, Harrison Brand¹⁴, Grace Schwartz¹¹, Rachel Nguyen¹⁵, Elizabeth E Guerrero¹⁶, Caroline Dias¹⁷; Autism Sequencing Consortium; iPSYCH-Broad Consortium; Catalina Betancur¹⁸, Edwin H Cook¹⁹, Louise Gallagher²⁰, Michael Gill²⁰, James S Sutcliffe²¹, Audrey Thurm²², Michael E Zwick²³, Anders D Børglum²⁴, Matthew W State¹¹, A Ercument Cicek²⁵, Michael E Talkowski¹⁴, David J Cutler²³, Bernie Devlin⁸, Stephan J Sanders²⁶, Kathryn Roeder²⁷, Mark J Daly²⁸, Joseph D Buxbaum²⁹

Collaborators

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

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Autistic Disorder / genetics*
Case-Control Studies
Cell Lineage
Cerebral Cortex / growth & development*
Cohort Studies
Exome
Exome Sequencing / methods*
Female
Gene Expression Regulation, Developmental*
Gene Frequency
Genetic Predisposition to Disease
Humans
Male
Mutation, Missense
Neurobiology / methods*
Neurons / metabolism
Phenotype
Sex Factors
Single-Cell Analysis / methods

Abstract

Publication types

MeSH terms

Grants and funding