The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.
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Hadley, Dexter | Wu, Zhi Liang | Kao, Charlly | Kini, Akshata | Mohamed-Hadley, Alisha | Thomas, Kelly | Vazquez, Lyam | Qiu, Haijun | Mentch, Frank | Pellegrino, Renata | Kim, Cecilia | Connolly, John | Pinto, Dalila | Merikangas, Alison | Klei, Lambertus | Vorstman, Jacob | Thompson, Ann | Regan, Regina | Pagnamenta, Alistair, T. | Oliveira, Barbara | Magalhaes, Tiago, R. | Gilbert, John | Duketis, Eftichia | de Jonge, Maretha, V. | Cuccaro, Michael | Correia, Catarina | Conroy, Judith | Conceição, Inês, C. | Chiocchetti, Andreas, G. | Casey, Jillian | Bolshakova, Nadia | Bacchelli, Elena | Anney, Richard | Zwaigenbaum, Lonnie | Wittemeyer, Kerstin | Wallace, Simon | van Engeland, Herman | Soorya, Latha | Rogé, Bernadette | Roberts, Wendy | Poustka, Fritz | Mouga, Susana | Minshew, Nancy | Mcgrew, Susan, G. | Lord, Catherine | Leboyer, Marion | Le Couteur, Ann, S. | Kolevzon, Alexander | Jacob, Suma | Guter, Stephen | Green, Jonathan | Green, Andrew | Gillberg, Christopher | Fernandez, Bridget, A. | Duque, Frederico | Delorme, Richard | Dawson, Geraldine | Café, Cátia | Brennan, Sean | Bourgeron, Thomas | Bolton, Patrick, F. | Bölte, Sven | Bernier, Raphael | Baird, Gillian | Bailey, Anthony, J. | Anagnostou, Evdokia | Almeida, Joana | Wijsman, Ellen, M. | Vieland, Veronica, J. | Vicente, Astrid, M. | Schellenberg, Gerard, D. | Pericak-Vance, Margaret | Paterson, Andrew, D. | Parr, Jeremy, R. | Oliveira, Guiomar | Nurnberger, John, I. | Monaco, Anthony, P. | Maestrini, Elena | Klauck, Sabine, M. | Haines, Jonathan, L. | Geschwind, Daniel, H. | Freitag, Christine, M. | Folstein, Susan, E. | Ennis, Sean | Coon, Hilary | Battaglia, Agatino | Szatmari, Peter | Sutcliffe, James, S. | Hallmayer, Joachim | Gill, Michael | Cook, Edwin, H. | Buxbaum, Joseph, D. | Devlin, Bernie | Gallagher, Louise | Betancur, Catalina | Scherer, Stephen, W. | Glessner, Joseph | Hakonarson, Hakon
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CCSD ; Nature Publishing Group -
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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.
