Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Jennifer Howe; Anthony Griswold; John Gilbert; Eftichia Duketis; Beth Dombroski; Maretha De Jonge; Michael Cuccaro; Emily Crawford; Catarina Correia; Judith Conroy; Inês Conceição; Andreas Chiocchetti; Jillian Casey; Guiqing Cai; Christelle Cabrol; Nadia Bolshakova; Elena Bacchelli; Richard Anney; Steven Gallinger; Michelle Cotterchio; Graham Casey; Lonnie Zwaigenbaum; Kerstin Wittemeyer; Kirsty Wing; Simon Wallace; Herman Van Engeland; Ana Tryfon; Susanne Thomson; Latha Soorya; Bernadette Rogé; Wendy Roberts; Fritz Poustka; Susana Mouga; Nancy Minshew; Alison Mcinnes; Susan Mcgrew; Catherine Lord; Marion Leboyer; Ann Le Couteur; Alexander Kolevzon; Dalila Pinto; Patricia Jiménez González; Suma Jacob; Elsa Delaby; Daniele Merico; Richard Holt; Mafalda Barbosa; Stephen Guter; Alison Merikangas; Jonathan Green; Lambertus Klei; Andrew Green; Christopher Gillberg; Bhooma Thiruvahindrapuram; Xiao Xu; Bridget Fernandez; Robert Ziman; Frederico Duque; Zhuozhi Wang; Richard Delorme; Jacob Vorstman; Geraldine Dawson; Ann Thompson; Pauline Chaste; Regina Regan; Cátia Café; Marion Pilorge; Sean Brennan; Giovanna Pellecchia; Thomas Bourgeron; Alistair Pagnamenta; Patrick Bolton; Sven Bölte; Bárbara Oliveira; Christian Marshall; Raphael Bernier; Tiago Magalhaes; Gillian Baird; Jennifer Lowe; Anthony Bailey; Evdokia Anagnostou; Joana Almeida; Ellen Wijsman; Veronica Vieland; Astrid Vicente; Gerard Schellenberg; Margaret Pericak-Vance; Andrew Paterson; Jeremy Parr; Guiomar Oliveira; John Nurnberger; Anthony Monaco; Elena Maestrini; Sabine Klauck; Hakon Hakonarson; Jonathan Haines; Daniel Geschwind; Christine Freitag; Susan Folstein; Sean Ennis

doi:10.1016/j.ajhg.2014.03.018

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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

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Peer reviewed

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Jennifer Howe, Anthony Griswold, John Gilbert, Eftichia Duketis, Beth Dombroski, Maretha De Jonge, Michael Cuccaro, Emily Crawford, Catarina Correia, Judith Conroy, …

American journal of human genetics, Vol.94(5), pp.677-694

2014-05-01

DOI: https://doi.org/10.1016/j.ajhg.2014.03.018

PMCID: PMC4067558

PMID: 24768552

Abstract

Life Sciences

Genetics

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

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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: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
Creators: Jennifer Howe - Program in Genetics and Genomic Biology
Anthony Griswold - John P. Hussman Institute for Human Genomics
John Gilbert - John P. Hussman Institute for Human Genomics
Eftichia Duketis - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Beth Dombroski - Pathology and Laboratory Medicine
Maretha De Jonge - Department of Psychiatry
Michael Cuccaro - John P. Hussman Institute for Human Genomics
Emily Crawford - Vanderbilt Brain Institute
Catarina Correia - Instituto Nacional de Saude Dr Ricardo Jorge
Judith Conroy - Academic Centre on Rare Diseases
Inês Conceição - Instituto Nacional de Saude Dr Ricardo Jorge
Andreas Chiocchetti - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Jillian Casey - Academic Centre on Rare Diseases
Guiqing Cai - Departments of Psychiatry, Genetics and Genomic Sciences
Christelle Cabrol - Neurosciences Paris Seine
Nadia Bolshakova - Department of Psychiatry
Elena Bacchelli - Department of Pharmacy and Biotechnology
Richard Anney - Department of Psychiatry
Steven Gallinger - Familial Gastrointestinal Cancer Registry
Michelle Cotterchio - Prevention & Cancer Control
Graham Casey - Department of Preventive Medicine
Lonnie Zwaigenbaum - Department of Pediatrics
Kerstin Wittemeyer - School of Education
Kirsty Wing - The Wellcome Trust Centre for Human Genetics [Oxford]
Simon Wallace - Department of Psychiatry
Herman Van Engeland - Department of Psychiatry
Ana Tryfon - Department of Psychiatry
Susanne Thomson - Department of Molecular Physiology & Biophysics and Psychiatry
Latha Soorya - Department of Psychiatry
Bernadette Rogé - Octogone Unité de Recherche Interdisciplinaire
Wendy Roberts - Autism Research Unit
Fritz Poustka - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Susana Mouga - Unidade de Neurodesenvolvimento e Autismo
Nancy Minshew - Department of Psychiatry [Pittsburgh]
Alison Mcinnes - Department of Psychiatry
Susan Mcgrew - Department of Pediatrics
Catherine Lord - Center for Autism and the Developing Brain
Marion Leboyer - Institut Mondor de Recherche Biomédicale
Ann Le Couteur - Institute of Health and Society
Alexander Kolevzon - Department of Psychiatry
Dalila Pinto - Departments of Psychiatry, Genetics and Genomic Sciences
Patricia Jiménez González - Child Developmental and Behavioral Unit
Suma Jacob - Department of Psychiatry
Elsa Delaby - Neurosciences Paris Seine
Daniele Merico - Program in Genetics and Genomic Biology
Richard Holt - The Wellcome Trust Centre for Human Genetics [Oxford]
Mafalda Barbosa - Departments of Psychiatry, Genetics and Genomic Sciences
Stephen Guter - Department of Psychiatry
Alison Merikangas - Department of Psychiatry
Jonathan Green - Manchester Academic Health Sciences Centre
Lambertus Klei - Department of Psychiatry [Pittsburgh]
Andrew Green - Academic Centre on Rare Diseases
Christopher Gillberg - Gillberg Neuropsychiatry Centre [Göteborg, Sueden]
Bhooma Thiruvahindrapuram - Program in Genetics and Genomic Biology
Xiao Xu - Departments of Psychiatry, Genetics and Genomic Sciences
Bridget Fernandez - Memorial University of Newfoundland [St. John's]
Robert Ziman - Program in Genetics and Genomic Biology
Frederico Duque - Unidade de Neurodesenvolvimento e Autismo
Zhuozhi Wang - Program in Genetics and Genomic Biology
Richard Delorme - Génétique Humaine et Fonctions Cognitives
Jacob Vorstman - Department of Psychiatry
Geraldine Dawson - Department of Psychiatry and Behavioral Sciences
Ann Thompson - Department of Psychiatry and Behavioural Neurosciences
Pauline Chaste - Department of Psychiatry [Pittsburgh]
Regina Regan - Academic Centre on Rare Diseases
Cátia Café - Unidade de Neurodesenvolvimento e Autismo
Marion Pilorge - Neurosciences Paris Seine
Sean Brennan - Department of Psychiatry
Giovanna Pellecchia - Program in Genetics and Genomic Biology
Thomas Bourgeron - Génétique Humaine et Fonctions Cognitives
Alistair Pagnamenta - The Wellcome Trust Centre for Human Genetics [Oxford]
Patrick Bolton - Institute of Psychiatry
Sven Bölte - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Bárbara Oliveira - Instituto Nacional de Saude Dr Ricardo Jorge
Christian Marshall - Program in Genetics and Genomic Biology
Raphael Bernier - Department of Psychiatry and Behavioral Sciences
Tiago Magalhaes - Academic Centre on Rare Diseases
Gillian Baird - Paediatric Neurodisability
Jennifer Lowe - Department of Neurology
Anthony Bailey - MRC Social, Genetic and Developmental Psychiatry Centre
Evdokia Anagnostou - Bloorview Research Institute
Joana Almeida - Unidade de Neurodesenvolvimento e Autismo
Ellen Wijsman - Division of Medical Genetics [Seattle]
Veronica Vieland - Battelle Center for Mathematical Medicine
Astrid Vicente - Instituto Nacional de Saude Dr Ricardo Jorge
Gerard Schellenberg - Pathology and Laboratory Medicine
Margaret Pericak-Vance - John P. Hussman Institute for Human Genomics
Andrew Paterson - Program in Genetics and Genomic Biology
Jeremy Parr - Institute of Neuroscience [Newcastle]
Guiomar Oliveira - Unidade de Neurodesenvolvimento e Autismo
John Nurnberger - Department of Psychiatry
Anthony Monaco - The Wellcome Trust Centre for Human Genetics [Oxford]
Elena Maestrini - Department of Pharmacy and Biotechnology
Sabine Klauck - Division of Molecular Genome Analysis
Hakon Hakonarson - The Center for Applied Genomics
Jonathan Haines - Vanderbilt Brain Institute
Daniel Geschwind - Department of Neurology
Christine Freitag - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Susan Folstein - John P. Hussman Institute for Human Genomics
Sean Ennis - Academic Centre on Rare Diseases
Publication Details: American journal of human genetics, Vol.94(5), pp.677-694
Publisher: Elsevier (Cell Press)
Academic Unit: Miller School of Medicine; UMMG Department of Pathology; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24768552
PMCID: PMC4067558
Record Identifier: 991031560959702976