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

Lookup NU author(s): Professor Ann Le Couteur, Professor Jeremy Parr

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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 4.16 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. © 2014 Macmillan Publishers Limited. All rights reserved.


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Author(s): Hadley D, Wu Z-L, Kao C, Kini A, Mohamed-Hadley A, Thomas K, Vazquez L, Qiu H, Mentch F, Pellegrino R, Kim C, Connolly J, Glessner J, Hakonarson H, Pinto D, Merikangas A, Klei L, Vorstman JAS, Thompson A, Regan R, Pagnamenta AT, Oliveira B, Magalhaes TR, Gilbert J, Duketis E, De Jonge MV, Cuccaro M, Correia CT, Conroy J, Conceica IC, Chiocchetti AG, Casey JP, Bolshakova N, Bacchelli E, Anney R, Zwaigenbaum L, Wittemeyer K, Wallace S, Van Engeland H, Soorya L, Roge B, Roberts W, Poustka F, Mouga S, Minshew N, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jacob S, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Brennan S, Bourgeron T, Bolton PF, Bolte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg ED, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Almeida J, Cafe C, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2014

Volume: 5

Online publication date: 13/06/2014

Acceptance date: 07/05/2014

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

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

DOI: 10.1038/ncomms5074

PubMed id: 24927284


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