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

• DOI: 10.1038/ncomms5074
• Publication Date: 2014-06-13T09:24:36Z
• Authors: Dexter Hadley; Zhi-liang Wu; Charlly Kao; Akshata Kini; Alisha Mohamed-Ha...; Kelly Thomas; Lyam Vazquez; Haijun Qiu; Frank Mentch; Renata Pellegrino; Cecilia Kim; John Connolly; ; Dalila Pinto; Alison Merikangas; Lambertus Klei; Jacob A.S. Vorstman; Ann Thompson; Regina Regan; Alistair T. Pagna...; Bárbara Oliveira; Tiago R. Magalhaes; John Gilbert; Eftichia Duketis; Maretha V. De Jonge; Michael Cuccaro; Catarina T. Correia; Judith Conroy; Inês C. Conceição; Andreas G. Chiocc...; Jillian P. 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 G. McGrew; Catherine Lord; Marion Leboyer; Ann S. Le Couteur; Alexander Kolevzon; Suma Jacob; Stephen Guter; Jonathan Green; Andrew Green; Christopher Gillberg; Bridget A. Fernandez; Frederico Duque; Richard Delorme; Geraldine Dawson; Cátia Café; Sean Brennan; Thomas Bourgeron; Patrick F. Bolton; Sven Bölte; Raphael Bernier; Gillian Baird; Anthony J. Bailey; Evdokia Anagnostou; Joana Almeida; Ellen M. Wijsman; Veronica J. Vieland; Astrid M. Vicente; Gerard D. Schelle...; Margaret Pericak-...; Andrew D. Paterson; Jeremy R. Parr; Guiomar Oliveira; Joana Almeida; Cátia Café; Susana Mouga; Catarina Correia; John I. Nurnberger; Anthony P. Monaco; Elena Maestrini; Sabine M. Klauck; Hakon Hakonarson; 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; Hakon Hakonarson
• Keywords: Male; 570; DNA Copy Number Variations; Intellectual and Developmental Disabilities (IDD); Autism; 610; [SDV.GEN] Life Sciences [q-bio]/Genetics; AGP Consortium; Receptors, Metabotropic Glutamate; Article; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; Calmodulin; Receptors; Genetics; Metabotropic Glutamate; 2.1 Biological and endogenous factors; Humans; Gene Regulatory Networks; Aetiology; Autistic Disorder; Preschool; Child; Pediatric; [SDV.GEN]Life Sciences [q-bio]/Genetics; 0303 health sciences; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Neurosciences; Brain Disorders; 3. Good health; Mental Health; 5.1 Pharmaceuticals; Child, Preschool; Mental health; Female; Development of treatments and therapeutic interventions

AbstractAlthough 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.