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Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

By Josephine Elia, Joseph T Glessner, Kai Wang, Nagahide Takahashi, Corina J Shtir, Dexter Hadley, Patrick M A Sleiman, Haitao Zhang, Cecilia E Kim, Reid Robison, Gholson J Lyon, James H Flory, Jonathan P Bradfield, Marcin Imielinski, Cuiping Hou, Edward C Frackelton, Rosetta M Chiavacci, Takeshi Sakurai, Cara Rabin, Frank A Middleton, Kelly A Thomas, Maria Garris, Frank Mentch, Christine M Freitag, Hans-Christoph Steinhausen, Alexandre A Todorov, Andreas Reif, Aribert Rothenberger, Barbara Franke, Eric O Mick, Herbert Roeyers, Jan Buitelaar, Klaus-Peter Lesch, Tobias Banaschewski, Richard P Ebstein, Fernando Mulas, Robert D Oades, Joseph Sergeant, Edmund Sonuga-Barke, Tobias J Renner, Marcel Romanos, Jasmin Romanos, Andreas Warnke, Susanne Walitza, Jobst Meyer, Haukur Pálmason, Christiane Seitz, Sandra K Loo, Susan L Smalley, Joseph Biederman, Lindsey Kent, Philip Asherson, Richard J L Anney, J William Gaynor, Philip Shaw, Marcella Devoto, Peter S White, Struan F A Grant, Joseph D Buxbaum, Judith L Rapoport, Nigel M Williams, Stanley F Nelson, Stephen V Faraone and Hakon Hakonarson


To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.US National Institutes of Health (NIH) R01MH62873 NIH K23MH066275 Pfizer CHOP University of Pennsylvania National Center for Research Resources UL1-RR-024134 Cotswold Foundation US Department of Health and Human Services 1RC2MH089924 Seaver Foundation NIMH P50MH066392 Deutsche Forschungsgemeinschaft KFO 125 SFB 581 SFB TRR 58 ME 1923/5-1 ME 1923/5-3 Bundesministerium fur Bildung und Forschung (BMBF) 01GV060

Topics: Attention Deficit Disorder with Hyperactivity, Child, Child, Preschool, DNA Copy Number Variations, Gene Deletion, Gene Regulatory Networks, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Receptors, Metabotropic Glutamate
Publisher: Nature Publishing Group
Year: 2012
DOI identifier: 10.1038/ng.1013
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