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

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. MiddletonKelly 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, Hakon Hakonarson

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247 Scopus citations

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.

Original languageEnglish
Pages (from-to)78-84
Number of pages7
JournalNature Genetics
Volume44
Issue number1
DOIs
StatePublished - Jan 2012

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