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

• Published in: Nature communications Vol. 5; no. 1; p. 4074
• Main 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, Glessner, Joseph, Hakonarson, Hakon
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.06.2014; Nature Pub. Group
• Subjects: Autistic Disorder - genetics; Autistic Disorder - metabolism; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Calmodulin - genetics; Calmodulin - metabolism; Child; Child, Preschool; DNA Copy Number Variations; Female; Gene Regulatory Networks; Genetics; Humans; Life Sciences; Male; Neurosciences; Neurovetenskaper; Proto-Oncogene Proteins c-myc - genetics; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5074

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.