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

2014; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/ncomms5074

2041-1723

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 J. Connolly, Dalila Pinto, Alison Merikangas, Lambertus Klei, Jacob Vorstman, Ann Thompson, Regina Regan, Alistair T. Pagnamenta, Bárbara Oliveira, Tiago R. Magalhães, John R. Gilbert, Eftichia Duketis, Maretha Jonge, Michael L. Cuccaro, Catarina Correia, Judith Conroy, Inês C. Conceição, Andreas G. Chiocchetti, Jillian P. Casey, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Simon Wallace, Hermán van Engeland, Latha Soorya, Bernadette Rogé, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy J. Minshew, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann S. Couteur, Alexander Kolevzon, Suma Jacob, Stephen J. Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Géraldine Dawson, Cátia Café, S. Brennan, Thomas Bourgeron, Patrick Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony Bailey, Evdokia Anagnostou, Joana Almeida, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Gerard D. Schellenberg, Margaret A. Pericak‐Vance, Andrew D. Paterson, Jeremy Parr, Guiomar Oliveira, Joana Almeida, Cátia Café, Susana Mouga, Catarina Correia, John I. Nürnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Hákon Hákonarson, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer, Joseph Glessner, Hákon Hákonarson,

Genetics and Neurodevelopmental Disorders

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.