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Synaptic, transcriptional and chromatin genes disrupted in autism

Author

Listed:
  • Silvia De Rubeis

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Xin He

    (Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University)

  • Arthur P. Goldberg

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Christopher S. Poultney

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Kaitlin Samocha

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital)

  • A. Ercument Cicek

    (Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University)

  • Yan Kou

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Li Liu

    (Carnegie Mellon University)

  • Menachem Fromer

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Analytic and Translational Genetics Unit, Massachusetts General Hospital)

  • Susan Walker

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.)

  • Tarjinder Singh

    (The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.)

  • Lambertus Klei

    (University of Pittsburgh School of Medicine)

  • Jack Kosmicki

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital)

  • Shih-Chen Fu

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Branko Aleksic

    (Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.)

  • Monica Biscaldi

    (Psychotherapy, and Psychosomatics, University Medical Center Freiburg; Center for Mental Disorders, 79106 Freiburg, Germany.
    Center for Mental Disorders, 79106 Freiburg, Germany.)

  • Patrick F. Bolton

    (King’s College London Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.)

  • Jessica M. Brownfeld

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Jinlu Cai

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Nicholas G. Campbell

    (Vanderbilt Brain Institute, Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Angel Carracedo

    (Genomic Medicine Group, CIBERER, University of Santiago de Compostela and Galician Foundation of Genomic Medicine (SERGAS), 15706 Santiago de Compostela, Spain.
    Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.)

  • Maria H. Chahrour

    (Harvard Medical School
    Boston Children’s Hospital)

  • Andreas G. Chiocchetti

    (Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.)

  • Hilary Coon

    (University of Utah
    University of Utah)

  • Emily L. Crawford

    (Vanderbilt Brain Institute, Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Lucy Crooks

    (The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.)

  • Sarah R. Curran

    (King’s College London Institute of Psychiatry, Psychology & Neuroscience, London, SE5 8AF, UK.)

  • Geraldine Dawson

    (Duke Institute for Brain Sciences, Duke University)

  • Eftichia Duketis

    (Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.)

  • Bridget A. Fernandez

    (Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s, Newfoundland A1B 3V6, Canada.)

  • Louise Gallagher

    (School of Medicine, Trinity College Dublin, Dublin 8, Ireland.)

  • Evan Geller

    (University of Pennsylvania Perelman School of Medicine)

  • Stephen J. Guter

    (Institute for Juvenile Research, University of Illinois at Chicago)

  • R. Sean Hill

    (Harvard Medical School
    Boston Children’s Hospital)

  • Iuliana Ionita-Laza
  • Patricia Jimenez Gonzalez

    (Hospital Nacional de Niños Dr Saenz Herrera, CCSS, Child Developmental and Behavioral Unit)

  • Helena Kilpinen

    (European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.)

  • Sabine M. Klauck

    (German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.)

  • Alexander Kolevzon

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Irene Lee

    (Institute of Child Health, University College London, London, WC1N 1EH, UK.)

  • Jing Lei

    (Carnegie Mellon University)

  • Terho Lehtimäki

    (Fimlab Laboratories, SF-33100 Tampere, Finland.)

  • Chiao-Feng Lin

    (University of Pennsylvania Perelman School of Medicine)

  • Avi Ma’ayan

    (Icahn School of Medicine at Mount Sinai)

  • Christian R. Marshall

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.)

  • Alison L. McInnes

    (Department of Psychiatry Kaiser Permanente)

  • Benjamin Neale

    (The Broad Institute of MIT and Harvard)

  • Michael J. Owen

    (MRC Centre for Neuropsychiatric Genetics and Genomics, and the Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, CF24 4HQ, UK.)

  • Norio Ozaki

    (Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.)

  • Mara Parellada

    (Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Universidad Complutense, 28040 Madrid, Spain.)

  • Jeremy R. Parr

    (Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.)

  • Shaun Purcell

    (Icahn School of Medicine at Mount Sinai)

  • Kaija Puura

    (University of Tampere and Tampere University Hospital, 33521 Tampere, Finland SF-33101.)

  • Deepthi Rajagopalan

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.)

  • Karola Rehnström

    (The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.)

  • Abraham Reichenberg

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Aniko Sabo

    (Baylor College of Medicine)

  • Michael Sachse

    (Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.)

  • Stephan J. Sanders

    (University of California at San Francisco)

  • Chad Schafer

    (Carnegie Mellon University)

  • Martin Schulte-Rüther

    (Psychosomatics, and Psychotherapy, Translational Brain Medicine in Psychiatry and Neurology, University Hospital RWTH Aachen / JARA Brain Translational Medicine, 52056 Aachen, Germany.)

  • David Skuse

    (Institute of Child Health, University College London, London, WC1N 1EH, UK.
    Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, WC1N 3JH, UK.)

  • Christine Stevens

    (The Broad Institute of MIT and Harvard)

  • Peter Szatmari

    (Offord Centre for Child Studies, McMaster University, Hamilton, Ontario L8S 4K1, Canada.)

  • Kristiina Tammimies

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.)

  • Otto Valladares

    (University of Pennsylvania Perelman School of Medicine)

  • Annette Voran

    (Saarland University Hospital, D-66424 Homburg, Germany.)

  • Li-San Wang

    (University of Pennsylvania Perelman School of Medicine)

  • Lauren A. Weiss

    (University of California at San Francisco)

  • A. Jeremy Willsey

    (University of California at San Francisco)

  • Timothy W. Yu

    (Harvard Medical School
    Boston Children’s Hospital)

  • Ryan K. C. Yuen

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.)

  • Edwin H. Cook

    (Institute for Juvenile Research, University of Illinois at Chicago)

  • Christine M. Freitag

    (Psychosomatics and Psychotherapy, Goethe University Frankfurt, 60528 Frankfurt, Germany.)

  • Michael Gill

    (School of Medicine, Trinity College Dublin, Dublin 8, Ireland.)

  • Christina M. Hultman

    (Karolinska Institutet, SE-171 77 Stockholm, Sweden.)

  • Thomas Lehner

    (National Institute of Mental Health, National Institutes of Health)

  • Aarno Palotie

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
    Institute for Molecular Medicine Finland, University of Helsinki, FI-00014 Helsinki, Finland.
    Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.)

  • Gerard D. Schellenberg

    (University of Pennsylvania Perelman School of Medicine)

  • Pamela Sklar

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Matthew W. State

    (University of California at San Francisco)

  • James S. Sutcliffe

    (Vanderbilt Brain Institute, Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Christopher A. Walsh

    (Harvard Medical School
    Boston Children’s Hospital)

  • Stephen W. Scherer

    (Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
    McLaughlin Centre, University of Toronto, Toronto, Ontario M5S 1A1, Canada.)

  • Michael E. Zwick

    (Emory University School of Medicine)

  • Jeffrey C. Barrett

    (The Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.)

  • David J. Cutler

    (Emory University School of Medicine)

  • Kathryn Roeder

    (Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University
    Carnegie Mellon University)

  • Bernie Devlin

    (University of Pittsburgh School of Medicine)

  • Mark J. Daly

    (Harvard Medical School
    The Broad Institute of MIT and Harvard
    Center for Human Genetic Research, Massachusetts General Hospital)

  • Joseph D. Buxbaum

    (Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR)

Suggested Citation

  • Silvia De Rubeis & Xin He & Arthur P. Goldberg & Christopher S. Poultney & Kaitlin Samocha & A. Ercument Cicek & Yan Kou & Li Liu & Menachem Fromer & Susan Walker & Tarjinder Singh & Lambertus Klei & , 2014. "Synaptic, transcriptional and chromatin genes disrupted in autism," Nature, Nature, vol. 515(7526), pages 209-215, November.
    • Handle: RePEc:nat:nature:v:515:y:2014:i:7526:d:10.1038_nature13772
    DOI: 10.1038/nature13772
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    Cited by:

    1. Marieke Meijer & Miriam Öttl & Jie Yang & Aygul Subkhangulova & Avinash Kumar & Zicheng Feng & Torben W. Voorst & Alexander J. Groffen & Jan R. T. Weering & Yongli Zhang & Matthijs Verhage, 2024. "Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Saeede Salehi & Abdolhossein Zare & Gianluca Prezza & Jakob Bader & Cornelius Schneider & Utz Fischer & Felix Meissner & Matthias Mann & Michael Briese & Michael Sendtner, 2023. "Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Luye Qin & Jamal B. Williams & Tao Tan & Tiaotiao Liu & Qing Cao & Kaijie Ma & Zhen Yan, 2021. "Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Christina Kyrousi & Adam C. O’Neill & Agnieska Brazovskaja & Zhisong He & Pavel Kielkowski & Laure Coquand & Rossella Giaimo & Pierpaolo D’ Andrea & Alexander Belka & Andrea Forero Echeverry & Davide , 2021. "Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    5. Carolina Gracia-Diaz & Yijing Zhou & Qian Yang & Reza Maroofian & Paula Espana-Bonilla & Chul-Hwan Lee & Shuo Zhang & Natàlia Padilla & Raquel Fueyo & Elisa A. Waxman & Sunyimeng Lei & Garrett Otrimsk, 2023. "Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Ken-ichi Dewa & Nariko Arimura & Wataru Kakegawa & Masayuki Itoh & Toma Adachi & Satoshi Miyashita & Yukiko U. Inoue & Kento Hizawa & Kei Hori & Natsumi Honjoya & Haruya Yagishita & Shinichiro Taya & , 2024. "Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Takeo Kubota & Kazuki Mochizuki, 2016. "Epigenetic Effect of Environmental Factors on Autism Spectrum Disorders," IJERPH, MDPI, vol. 13(5), pages 1-12, May.
    8. Hyoseon Oh & Suho Lee & Yusang Oh & Seongbin Kim & Young Seo Kim & Yeji Yang & Woochul Choi & Ye-Eun Yoo & Heejin Cho & Seungjoon Lee & Esther Yang & Wuhyun Koh & Woojin Won & Ryunhee Kim & C. Justin , 2023. "Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    9. Sheng Wang & Belinda Wang & Vanessa Drury & Sam Drake & Nawei Sun & Hasan Alkhairo & Juan Arbelaez & Clif Duhn & Vanessa H. Bal & Kate Langley & Joanna Martin & Pieter J. Hoekstra & Andrea Dietrich & , 2023. "Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Stefano Berto & Alex H. Treacher & Emre Caglayan & Danni Luo & Jillian R. Haney & Michael J. Gandal & Daniel H. Geschwind & Albert A. Montillo & Genevieve Konopka, 2022. "Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. Bhagavathi Sundaram Sivamaruthi & Natarajan Suganthy & Periyanaina Kesika & Chaiyavat Chaiyasut, 2020. "The Role of Microbiome, Dietary Supplements, and Probiotics in Autism Spectrum Disorder," IJERPH, MDPI, vol. 17(8), pages 1-16, April.
    12. Marco Colizzi & Riccardo Bortoletto & Rosalia Costa & Sagnik Bhattacharyya & Matteo Balestrieri, 2022. "The Autism–Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System," IJERPH, MDPI, vol. 19(9), pages 1-22, May.
    13. Xinhong Chen & Damien A. Wolfe & Dhanesh Sivadasan Bindu & Mengying Zhang & Naz Taskin & David Goertsen & Timothy F. Shay & Erin E. Sullivan & Sheng-Fu Huang & Sripriya Ravindra Kumar & Cynthia M. Aro, 2023. "Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    14. Iva Salamon & Yongkyu Park & Terezija Miškić & Janja Kopić & Paul Matteson & Nicholas F. Page & Alfonso Roque & Geoffrey W. McAuliffe & John Favate & Marta Garcia-Forn & Premal Shah & Miloš Judaš & Ja, 2023. "Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    15. Marc P. Forrest & Marc Dos Santos & Nicolas H. Piguel & Yi-Zhi Wang & Nicole A. Hawkins & Vikram A. Bagchi & Leonardo E. Dionisio & Sehyoun Yoon & Dina Simkin & Maria Dolores Martin-de-Saavedra & Ruoq, 2023. "Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    16. Pu-Yun Shih & Yu-Lun Fang & Sahana Shankar & Sue-Ping Lee & Hsiao-Tang Hu & Hsin Chen & Ting-Fang Wang & Kuo-Chiang Hsia & Yi-Ping Hsueh, 2022. "Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    17. Emad Mohammad ali & Fatimah eid ziad Al- Adwan & Yazan M. Al-Naimat, 2019. "Autism Spectrum Disorder (ASD); Symptoms, Causes, Diagnosis, Intervention, and Counseling Needs of the Families in Jordan," Modern Applied Science, Canadian Center of Science and Education, vol. 13(5), pages 1-48, May.

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