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

Dexter Hadley,Lyam Vazquez,Alisha Mohamed-Hadley,Cecilia Kim,Renata Pellegrino,Charlly Kao,Kelly Thomas,Frank Mentch,Haijun Qiu,Akshata Kini,Zhi-Liang Wu,John J Connolly ,Joseph T Glessner ,Hákon Hákonarson

doi:10.1038/ncomms5074

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.

Highlights

Multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities
We find other attractive candidates such as the MAX dimerization protein (MXD) network that is implicated in cancer, and a Calmodulin 1 (CALM1) gene interaction network that is active in neuronal tissues
After cleaning the data to remove sample duplicates and performing standard QC for copy-number variants (CNVs), we first inferred the continental ancestry of 5,627 affected cases and 9,644 disease-free controls using a training set defined by populations from HapMap 3 and the Human Genome Diversity Panel[46] (Table 1)

Summary

Introduction

Multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. We find multiple defective networks in the ASDs, most notably rare copy-number variants (CNVs) in the metabotropic glutamate receptor (mGluR) signalling pathway in 5.8% of patients with the ASDs. Defective mGluR signalling was found in both ADHD30 and schizophrenia[31,32,33,34,35,36], two common neuropsychiatric disorders that are highly coincident with the ASDs. we find other attractive candidates such as the MAX dimerization protein (MXD) network that is implicated in cancer, and a Calmodulin 1 (CALM1) gene interaction network that is active in neuronal tissues.

Results

Conclusion