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, Hakon Hakonarson, Dalila Pinto, Alison Merikangas, Lambertus Klei, Jacob A.S. Vorstman, Ann Thompson, Regina ReganAlistair T. Pagnamenta, Bárbara Oliveira, Tiago R. Magalhaes, John Gilbert, Eftichia Duketis, Maretha V. De Jonge, Michael Cuccaro, Catarina T. Correia, Judith Conroy, Inês C. Conceiça, Andreas G. Chiocchetti, Jillian P. Casey, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Simon Wallace, Herman Van Engeland, Latha Soorya, Bernadette Rogé, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy Minshew, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann S. Le Couteur, Alexander Kolevzon, Suma Jacob, Stephen Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Erard D. Schellenberg, Margaret Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, Joana Almeida, Cátia Café, John I. Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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 4.16 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.

Original languageEnglish (US)
Article number4074
JournalNature communications
Volume5
DOIs
StatePublished - Jun 13 2014

Bibliographical note

Funding Information:
We thank all study participants and their families. We thank all the staff at the Center for Applied Genomics at CHOP for their invaluable contributions to recruitment of study subjects and genotyping of samples. We also gratefully acknowledge the resources provided by the AGRE Consortium and their participating families, and by the Autism Genome Project (AGP) Consortium and their participating families. 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). AGRE-approved academic researchers can acquire the data sets from AGRE at http://www.agre.org. There were 1,693 cases of the full AGP data sets that were genotyped by the AGP consortium. The full AGP data sets are made available from dbGaP at http://www.ncbi.nlm.nih.gov/gap. The remaining 5,049 cases and all 12,544 controls were all genotyped by the Center for Applied Genomics at the Children’s Hospital of Philadelphia.

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