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

Hadley, D. et al. (2014) The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism. Nature Communications, 5, 4074. (doi: 10.1038/ncomms5074) (PMID:24927284) (PMCID:PMC4059929)

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 ≤ 4.16E-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.

• Item Type: Articles
• Additional Information: The study was funded by an Institutional Development Fund from The Children’s Hospital of Philadelphia; The Margaret Q Landenberger Foundation; The Lurie Family Foundation; The Kubert Estate Fund and by U01HG005830. AGRE is a program of Autism Speaks and is at present supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to C.M. Lajonchere (PI) and formerly by grant MH64547 to D.H. Geschwind (PI).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gillberg, Professor Christopher
• Authors: 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., AGP Consortium, ., and ,
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2014 Macmillan Publishers Ltd
• First Published: First published in Nature Communications 5:4074
• Publisher Policy: Reproduced under a creative commons licence