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

Dexter Hadley; Zhi Liang Wu; Charlly Kao; Akshata Kini; Alisha Mohamed-Hadley; Kelly Thomas; Lyam Vazquez; Haijun Qiu; Frank Mentch; Renata Pellegrino; Cecilia Kim; John Connolly; Dalila Pinto; Alison Merikangas; Lambertus Klei; Jacob Vorstman; Ann Thompson; Regina Regan; Alistair Pagnamenta; Barbara Oliveira; 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; Fritz Poustka; Susana Mouga; Nancy Minshew; Susan Mcgrew; Catherine Lord; Marion Leboyer; Ann Le Couteur; Alexander Kolevzon; Suma Jacob; Stephen Guter; Jonathan Green; Andrew Green; Christopher Gillberg; Bridget Fernandez; Frederico Duque; Richard Delorme; Geraldine Dawson; Cátia Café; Sean Brennan; 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

doi:10.1038/ncomms5074

Journal articles

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

Dexter Hadley ¹ Zhi Liang Wu ¹ Charlly Kao ¹ Akshata Kini ¹ Alisha Mohamed-Hadley ¹ Kelly Thomas ¹ Lyam Vazquez ¹ Haijun Qiu ¹ Frank Mentch ¹ Renata Pellegrino ¹ Cecilia Kim ¹ John Connolly ¹ Dalila Pinto ^{2, 3, 4, 5, 6, 7} Alison Merikangas ⁸ Lambertus Klei ⁹ Jacob Vorstman ¹⁰ Ann Thompson ¹¹ Regina Regan ^{12, 13} Alistair Pagnamenta ¹⁴ Barbara Oliveira ^{15, 16} Tiago Magalhaes ^{12, 13} John Gilbert ¹⁷ Eftichia Duketis ¹⁸ Maretha de Jonge ¹⁰ Michael Cuccaro ¹⁷ Catarina Correia ^{15, 16} Judith Conroy ^{12, 19} Inês Conceição ^{15, 16} Andreas Chiocchetti ¹⁸ Jillian Casey ^{12, 13} Nadia Bolshakova ⁸ Elena Bacchelli ²⁰ Richard Anney ⁸ Lonnie Zwaigenbaum ²¹ Kerstin Wittemeyer ²² Simon Wallace ²³ Herman van Engeland ¹⁰ Latha Soorya ^{2, 3} Bernadette Rogé ²⁴ Wendy Roberts ²⁵ Fritz Poustka ¹⁸ Susana Mouga ^{26, 27} Nancy Minshew ⁹ Susan Mcgrew ²⁸ Catherine Lord ²⁹ Marion Leboyer ^{30, 31, 32} Ann Le Couteur ³³ Alexander Kolevzon ^{2, 3, 7} Suma Jacob ³⁴ Stephen Guter ³⁴ Jonathan Green ^{35, 36} Andrew Green ^{12, 37} Christopher Gillberg ³⁸ Bridget Fernandez ³⁹ Frederico Duque ^{26, 27} Richard Delorme ^{32, 40, 41} Geraldine Dawson ⁴² Cátia Café ²⁶ Sean Brennan ⁸ Thomas Bourgeron ^{32, 40, 43} Patrick Bolton ^{44, 45} Sven Bölte ¹⁸ Raphael Bernier ⁴⁶ Gillian Baird ⁴⁷ Anthony Bailey ^{48, 49} Evdokia Anagnostou ⁵⁰ Joana Almeida ²⁶ Ellen Wijsman ^{51, 52} Veronica Vieland ⁵³ Astrid Vicente ^{15, 54} Gerard Schellenberg ⁵⁵ Margaret Pericak-Vance ¹⁷ Andrew Paterson ⁵⁶ Jeremy Parr ⁵⁷ Guiomar Oliveira ^{26, 27} John Nurnberger ⁵⁸ Anthony Monaco ¹⁴ Elena Maestrini ²⁰ Sabine Klauck ⁵⁹ Jonathan Haines ^{60, 61} Daniel Geschwind ⁶² Christine Freitag ¹⁸ Susan Folstein ⁶³ Sean Ennis ¹² Hilary Coon ⁶⁴ Agatino Battaglia ⁶⁵ Peter Szatmari ¹¹ James Sutcliffe ^{60, 61} Joachim Hallmayer ⁶⁶ Michael Gill ⁶⁷ Edwin Cook ⁶⁸ Joseph Buxbaum ^{69, 70, 71, 72, 73, 74} Bernie Devlin ⁹ Louise Gallagher ⁶⁷ Catalina Betancur ⁷⁵ Stephen Scherer ^{56, 76} Joseph Glessner ¹ Hakon Hakonarson ^{1, 77, *}

* Corresponding author

1 The Center for Applied Genomics

2 Seaver Autism Center for Research and Treatment

3 Department of Psychiatry

4 Department of Genetics and Genomic Sciences

5 The Mindich Child Health and Development Institute

6 The Icahn Institute for Genomics and Multiscale Biology

7 Friedman Brain Institute

8 Discipline of Psychiatry [Dublin]

9 Department of Psychiatry [Pittsburgh]

10 Department of Psychiatry

11 Department of Psychiatry and Behavioural Neurosciences

12 ACoRD - Academic Centre on Rare Diseases

13 National Children's Research Centre

14 The Wellcome Trust Centre for Human Genetics [Oxford]

15 Instituto Nacional de Saude Dr Ricardo Jorge

16 Center for Biodiversity, Functional & Integrative Genomics

17 John P. Hussman Institute for Human Genomics

18 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

19 Children's University Hospital

20 Department of Pharmacy and Biotechnology

21 Department of Pediatrics

22 School of Education

23 Department of Psychiatry

24 Octogone - Octogone Unité de Recherche Interdisciplinaire

25 Autism Research Unit

26 UNDA - Unidade de Neurodesenvolvimento e Autismo

27 Institute for Biomedical Imaging and Life Science

28 Department of Pediatrics

29 CADB - Center for Autism and the Developing Brain

30 IMRB - Institut Mondor de Recherche Biomédicale

31 Service de psychiatrie

32 Foundation Fondamental

33 Institute of Health and Society

34 Institute for Juvenile Research and Department of Psychiatry

35 Manchester Academic Health Sciences Centre

36 Institute of Brain, Behaviour and Mental Health

37 National Centre for Medical Genetics

38 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]

39 Disciplines of Genetics and Medicine

40 Génétique Humaine et Fonctions Cognitives

41 Service de psychopathologie de l'enfant et de l'adolescent

42 Department of Psychiatry and Behavioral Sciences

43 UPD7 - Université Paris Diderot - Paris 7

44 Institute of Psychiatry

45 Department of Child and Adolescent Psychiatry

46 Department of Psychiatry and Behavioral Sciences

47 Paediatric Neurodisability

48 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre

49 Department of Psychiatry

50 Bloorview Research Institute

51 Division of Medical Genetics [Seattle]

52 Departments of Biostatistics and Medicine

53 Battelle Center for Mathematical Medicine

54 BioFIG

55 Pathology and Laboratory Medicine

56 Program in Genetics and Genomic Biology

57 ION - Institute of Neuroscience [Newcastle]

58 Department of Psychiatry

59 Division of Molecular Genome Analysis

60 Vanderbilt Brain Institute

61 Department of Molecular Physiology & Biophysics and Psychiatry

62 Department of Neurology

63 Utah Autism Research Program

64 Department of Developmental Neuroscience

65 Department of Psychiatry

66 Department of Neuroscience

67 Department of Psychiatry

68 Institute for Juvenile Research

69 Departments of Psychiatry, Genetics and Genomic Sciences

70 Department of Psychiatry

71 Seaver Autism Center for Research and Treatment

72 Friedman Brain Institute

73 The Mindich Child Health and Development Institute

74 Department of Neuroscience

75 NPS - Neurosciences Paris Seine

76 McLaughlin Centre

77 Department of Pediatrics

Abstract : 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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Complete list of metadatas

https://www.hal.inserm.fr/inserm-01009668
Contributor : Catalina Betancur <>
Submitted on : Wednesday, June 18, 2014 - 2:01:49 PM
Last modification on : Monday, August 31, 2020 - 12:26:21 PM
Long-term archiving on: : Tuesday, April 11, 2017 - 7:27:24 AM

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