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; 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; 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

Back

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

Journal article

Open access

Peer reviewed

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, …

Cell (Cambridge), Vol.180(3), pp.568-584.e23

2020-02-06

DOI: https://doi.org/10.1016/j.cell.2019.12.036

PMID: 31981491

Abstract

exome sequencing

genetics

neurodevelopment

cytoskeleton

liability

excitatory-inhibitory balance

excitatory neurons

cell type

autism spectrum disorder

inhibitory neurons

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. [Display omitted] •102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR ≤ 0.1)•Most are expressed and enriched early in excitatory and inhibitory neuronal lineages•Most affect synapses or regulate other genes; how these roles dovetail is unknown•Some ASD genes alter early development broadly, others appear more specific to ASD Large-scale sequencing of patients with autism allows identification of over 100 putative ASD-associated genes, the majority of which are neuronally expressed, and investigation of distinct genetic influences on ASD compared with other neurodevelopmental disorders.

Files and links (1)

url

https://doi.org/10.1016/j.cell.2019.12.036View

Published (Version of record) Open

Metrics

8 Record Views

1026 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Highly Cited Paper

Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.136 Autism & Development Disorders; 1.136.283 Autism
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology
ESI research areas: Molecular Biology & Genetics

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Creators: F. Kyle Satterstrom - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jack A Kosmicki - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jiebiao Wang - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA
Michael S Breen - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Silvia De Rubeis - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Joon-Yong An - Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
Minshi Peng - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA
Ryan Collins - Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Jakob Grove - The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
Lambertus Klei - Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Christine Stevens - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jennifer Reichert - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Maureen S Mulhern - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Mykyta Artomov - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Sherif Gerges - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Brooke Sheppard - Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
Xinyi Xu - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Aparna Bhaduri - Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
Utku Norman - Computer Engineering Department, Bilkent University, Ankara, Turkey
Harrison Brand - Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Grace Schwartz - Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
Rachel Nguyen - Center for Autism Research and Translation, University of California, Irvine, Irvine, CA, USA
Elizabeth E Guerrero - MIND (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California, Davis, Davis, CA, USA
Caroline Dias - Division of Genetics, Boston Children’s Hospital, Boston, MA, USA
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
Catalina Betancur - Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France
Edwin H Cook - Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
Louise Gallagher - Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
Michael Gill - Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
James S Sutcliffe - Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA
Audrey Thurm - National Institute of Mental Health, NIH, Bethesda, MD, USA
Michael E Zwick - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Anders D Børglum - The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
Matthew W State - Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
A. Ercument Cicek - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA
Michael E Talkowski - Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
David J Cutler - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Bernie Devlin - Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Stephan J Sanders - Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA
Kathryn Roeder - Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA
Mark J Daly - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Joseph D Buxbaum - Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Publication Details: Cell (Cambridge), Vol.180(3), pp.568-584.e23
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 31981491
Record Identifier: 991031575644402976