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

Dexter Hadley, Zhi-liang Wu, Charlly Kao, Akshata Kini, Alisha Mohamed-Hadley, Kelly Thomas, Lyam Vazquez, Haijun Qiu, Frank Mentch, Renata Pellegrino, Cecilia Kim, John Connolly, Joseph Glessner and Hakon Hakonarson ()
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Dexter Hadley: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Zhi-liang Wu: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Charlly Kao: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Akshata Kini: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Alisha Mohamed-Hadley: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Kelly Thomas: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Lyam Vazquez: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Haijun Qiu: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Frank Mentch: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Renata Pellegrino: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Cecilia Kim: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
John Connolly: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Joseph Glessner: The Center for Applied Genomics, The Children’s Hospital of Philadelphia
Hakon Hakonarson: The Center for Applied Genomics, The Children’s Hospital of Philadelphia

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5074

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