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

TitleGenome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.
Publication TypeJournal Article
Year of Publication2012
AuthorsElia, J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, Sleiman PMA, Zhang H, Kim CE, Robison R, Lyon GJ, Flory JH, Bradfield JP, Imielinski M, Hou C, Frackelton EC, Chiavacci RM, Sakurai T, Rabin C, Middleton FA, Thomas KA, Garris M, Mentch F, Freitag CM, Steinhausen H-C, Todorov AA, Reif A, Rothenberger A, Franke B, Mick EO, Roeyers H, Buitelaar J, Lesch K-P, Banaschewski T, Ebstein RP, Mulas F, Oades RD, Sergeant J, Sonuga-Barke E, Renner TJ, Romanos M, Romanos J, Warnke A, Walitza S, Meyer J, Pálmason H, Seitz C, Loo SK, Smalley SL, Biederman J, Kent L, Asherson P, Anney RJL, Gaynor WJ, Shaw P, Devoto M, White PS, Grant SFA, Buxbaum JD, Rapoport JL, Williams NM, Nelson SF, Faraone SV, Hakonarson H
JournalNature genetics
Volume44
Issue1
Pagination78-84
Date Published2012 Jan
ISSN1546-1718
KeywordsAttention 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
Abstract

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.

DOI10.1001/archgenpsychiatry.2011.51
Alternate JournalNat. Genet.