title: The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.
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.
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dexter
authors.initials: D
authors.lastname: Hadley
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Wu
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Charlly
authors.initials: C
authors.lastname: Kao
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Akshata
authors.initials: A
authors.lastname: Kini
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alisha
authors.initials: A
authors.lastname: Mohamed-Hadley
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Thomas
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lyam
authors.initials: L
authors.lastname: Vazquez
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Qiu
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Mentch
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Pellegrino
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.affiliation: The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.affiliation: 1] The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA [2] Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002147:Calmodulin; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D018094:Receptors, Metabotropic Glutamate