The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Tiago Magalhaes; John Gilbert; Eftichia Duketis; Maretha De Jonge; Michael Cuccaro; Catarina Correia; Judith Conroy; Inês Conceição; Andreas Chiocchetti; Jillian Casey; Nadia Bolshakova; Elena Bacchelli; Richard Anney; Lonnie Zwaigenbaum; Kerstin Wittemeyer; Simon Wallace; Herman Van Engeland; Latha Soorya; Bernadette Rogé; Wendy Roberts; Dexter Hadley; Fritz Poustka; Zhi Liang Wu; Susana Mouga; Charlly Kao; Nancy Minshew; Akshata Kini; Susan Mcgrew; Alisha Mohamed-Hadley; Catherine Lord; Kelly Thomas; Marion Leboyer; Lyam Vazquez; Ann Le Couteur; Haijun Qiu; Alexander Kolevzon; Frank Mentch; Suma Jacob; Renata Pellegrino; Stephen Guter; Cecilia Kim; Jonathan Green; John Connolly; Andrew Green; Dalila Pinto; Christopher Gillberg; Alison Merikangas; Bridget Fernandez; Lambertus Klei; Frederico Duque; Jacob Vorstman; Richard Delorme; Ann Thompson; Geraldine Dawson; Regina Regan; Cátia Café; Sean Brennan; Alistair Pagnamenta; Barbara Oliveira; Thomas Bourgeron; Patrick Bolton; Sven Bölte; Raphael Bernier; Gillian Baird; 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; Jonathan Haines; Daniel Geschwind; Christine Freitag; Susan Folstein; Sean Ennis; Hilary Coon; Agatino Battaglia; Peter Szatmari; James Sutcliffe; Joachim Hallmayer; Michael Gill; Edwin Cook; Joseph Buxbaum; Bernie Devlin; Louise Gallagher; Catalina Betancur; Stephen Scherer; Joseph Glessner; Hakon Hakonarson; AGP Consortium

doi:10.1038/ncomms5074

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The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Journal article

Open access

Peer reviewed

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Tiago Magalhaes, John Gilbert, Eftichia Duketis, Maretha De Jonge, Michael Cuccaro, Catarina Correia, Judith Conroy, Inês Conceição, Andreas Chiocchetti, Jillian Casey, …

Nature communications, Vol.5(1), pp.4074-4074

2014

DOI: https://doi.org/10.1038/ncomms5074

PMCID: PMC4059929

PMID: 24927284

Abstract

Life Sciences

Genetics

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

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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: The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
Creators: Tiago Magalhaes - Academic Centre on Rare Diseases
John Gilbert - John P. Hussman Institute for Human Genomics
Eftichia Duketis - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Maretha De Jonge - Department of Psychiatry
Michael Cuccaro - John P. Hussman Institute for Human Genomics
Catarina Correia - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
Judith Conroy - Academic Centre on Rare Diseases
Inês Conceição - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
Andreas Chiocchetti - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Jillian Casey - Academic Centre on Rare Diseases
Nadia Bolshakova - Discipline of Psychiatry [Dublin]
Elena Bacchelli - Department of Pharmacy and Biotechnology
Richard Anney - Discipline of Psychiatry [Dublin]
Lonnie Zwaigenbaum - Department of Pediatrics
Kerstin Wittemeyer - School of Education
Simon Wallace - Department of Psychiatry
Herman Van Engeland - Department of Psychiatry
Latha Soorya - Seaver Autism Center for Research and Treatment
Bernadette Rogé - Octogone Unité de Recherche Interdisciplinaire
Wendy Roberts - Autism Research Unit
Dexter Hadley - The Center for Applied Genomics
Fritz Poustka - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Zhi Liang Wu - The Center for Applied Genomics
Susana Mouga - Unidade de Neurodesenvolvimento e Autismo
Charlly Kao - The Center for Applied Genomics
Nancy Minshew - Department of Psychiatry [Pittsburgh]
Akshata Kini - The Center for Applied Genomics
Susan Mcgrew - Department of Pediatrics
Alisha Mohamed-Hadley - The Center for Applied Genomics
Catherine Lord - Center for Autism and the Developing Brain
Kelly Thomas - The Center for Applied Genomics
Marion Leboyer - Institut Mondor de Recherche Biomédicale
Lyam Vazquez - The Center for Applied Genomics
Ann Le Couteur - Institute of Health and Society
Haijun Qiu - The Center for Applied Genomics
Alexander Kolevzon - Seaver Autism Center for Research and Treatment
Frank Mentch - The Center for Applied Genomics
Suma Jacob - Institute for Juvenile Research and Department of Psychiatry
Renata Pellegrino - The Center for Applied Genomics
Stephen Guter - Institute for Juvenile Research and Department of Psychiatry
Cecilia Kim - The Center for Applied Genomics
Jonathan Green - Manchester Academic Health Sciences Centre
John Connolly - The Center for Applied Genomics
Andrew Green - Academic Centre on Rare Diseases
Dalila Pinto - Seaver Autism Center for Research and Treatment
Christopher Gillberg - Gillberg Neuropsychiatry Centre [Göteborg, Sueden]
Alison Merikangas - Discipline of Psychiatry [Dublin]
Bridget Fernandez - Disciplines of Genetics and Medicine
Lambertus Klei - Department of Psychiatry [Pittsburgh]
Frederico Duque - Unidade de Neurodesenvolvimento e Autismo
Jacob Vorstman - Department of Psychiatry
Richard Delorme - Foundation Fondamental
Ann Thompson - Department of Psychiatry and Behavioural Neurosciences
Geraldine Dawson - Department of Psychiatry and Behavioral Sciences
Regina Regan - Academic Centre on Rare Diseases
Cátia Café - Unidade de Neurodesenvolvimento e Autismo
Sean Brennan - Discipline of Psychiatry [Dublin]
Alistair Pagnamenta - The Wellcome Trust Centre for Human Genetics [Oxford]
Barbara Oliveira - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]
Thomas Bourgeron - Foundation Fondamental
Patrick Bolton - Institute of Psychiatry
Sven Bölte - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Raphael Bernier - Department of Psychiatry and Behavioral Sciences
Gillian Baird - Paediatric Neurodisability
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 Saùde Dr Ricardo Jorge [Portugal]
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
Jonathan Haines - Vanderbilt Brain Institute
Daniel Geschwind - Department of Neurology
Christine Freitag - Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy
Susan Folstein - Utah Autism Research Program
Sean Ennis - Academic Centre on Rare Diseases
Hilary Coon - Department of Developmental Neuroscience
Agatino Battaglia - Department of Psychiatry and Behavioral Sciences [Stanford]
Peter Szatmari - Department of Psychiatry and Behavioural Neurosciences
James Sutcliffe - Vanderbilt Brain Institute
Joachim Hallmayer - Department of Neuroscience
Michael Gill - Department of Psychiatry
Edwin Cook - Institute for Juvenile Research
Joseph Buxbaum - Departments of Psychiatry, Genetics and Genomic Sciences
Bernie Devlin - Department of Psychiatry [Pittsburgh]
Louise Gallagher - Department of Psychiatry
Catalina Betancur - Neurosciences Paris Seine
Stephen Scherer - Program in Genetics and Genomic Biology
Joseph Glessner - The Center for Applied Genomics
Hakon Hakonarson - The Center for Applied Genomics
AGP Consortium
Publication Details: Nature communications, Vol.5(1), pp.4074-4074
Publisher: Nature Publishing Group
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: 24927284
PMCID: PMC4059929
Record Identifier: 991031597607702976