The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
Authors: 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 ,   AGP Consortium, Pinto Dalila , Merikangas Alison , Klei Lambertus , Vorstman Jacob A.S. , Thompson Ann , Regan Regina , Pagnamenta Alistair T. , Oliveira Bárbara , Magalhaes Tiago R. , Gilbert John , Duketis Eftichia , De Jonge Maretha V. , Cuccaro Michael , Correia Catarina T. , Conroy Judith , Conceição Inês C. , Chiocchetti Andreas G. , Casey Jillian P. , Bolshakova Nadia , Bacchelli Elena , Anney Richard , Zwaigenbaum Lonnie , Wittemeyer Kerstin , Wallace Simon , Engeland Herman van , 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 , Almeida Joana , Café Cátia , Mouga Susana , Correia Catarina , Nurnberger John I. , Monaco Anthony P. , Maestrini Elena , Klauck Sabine M. , Hakonarson Hakon , 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 
Published: June 2014

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.