Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder : Nature Genetics : Nature Publishing Group

Nature Genetics | Letter

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

• Josephine Elia,^{1, 2, 46}
• Joseph T Glessner,^{3, 46}
• Kai Wang,³
• Nagahide Takahashi,⁴
• Corina J Shtir,⁵
• Dexter Hadley,³
• Patrick M A Sleiman,³
• Haitao Zhang,³
• Cecilia E Kim,³
• Reid Robison,⁶
• Gholson J Lyon,⁶
• James H Flory,³
• Jonathan P Bradfield,³
• Marcin Imielinski,³
• Cuiping Hou,³
• Edward C Frackelton,³
• Rosetta M Chiavacci,³
• Takeshi Sakurai,⁴
• Cara Rabin,⁷
• Frank A Middleton,⁸
• Kelly A Thomas,³
• Maria Garris,³
• Frank Mentch,³
• Christine M Freitag,⁹
• Hans-Christoph Steinhausen,^{10, 11, 12}
• Alexandre A Todorov,¹³
• Andreas Reif,¹⁴
• Aribert Rothenberger,¹⁵
• Barbara Franke,^{16, 17}
• Eric O Mick,¹⁸
• Herbert Roeyers,¹⁹
• Jan Buitelaar,²⁰
• Klaus-Peter Lesch,¹⁴
• Tobias Banaschewski,²¹
• Richard P Ebstein,²²
• Fernando Mulas,²³
• Robert D Oades,²⁴
• Joseph Sergeant,²⁵
• Edmund Sonuga-Barke,^{26, 27, 28}
• Tobias J Renner,²⁹
• Marcel Romanos,^{29, 30}
• Jasmin Romanos,²⁹
• Andreas Warnke,²⁹
• Susanne Walitza,^{10, 29}
• Jobst Meyer,³¹
• Haukur Pálmason,³¹
• Christiane Seitz,³²
• Sandra K Loo,³³
• Susan L Smalley,³³
• Joseph Biederman,¹⁸
• Lindsey Kent,³⁴
• Philip Asherson,¹⁰
• Richard J L Anney,³⁵
• J William Gaynor,³⁶
• Philip Shaw,⁷
• Marcella Devoto,^{37, 38, 39, 40}
• Peter S White,^{41, 42}
• Struan F A Grant,^{3, 37, 38}
• Joseph D Buxbaum,⁴
• Judith L Rapoport,⁷
• Nigel M Williams,⁴³
• Stanley F Nelson,⁵
• Stephen V Faraone^{8, 44}
• & Hakon Hakonarson^{3, 36, 37, 45}
• et al.

• Affiliations
• Contributions
• Corresponding author

Journal name:

Nature Genetics

Year published:

(2011)

DOI:

doi:10.1038/ng.1013

Received

24 June 2011

Accepted

28 October 2011

Published online

04 December 2011

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.

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Figures at a glance

left

1. Figure 1: A deletion directly affecting GRM5 that is exclusive to cases with ADHD and that was replicated in the IMAGE and PUWMa studies.

   

   Four hemizygous deletions in GRM5 in cases with ADHD from the CHOP study that were replicated by two deletions and three larger deletions found in the IMAGE study and one deletion found in the PUWMa study. The SNP coverage of the Illumina 550K, Perlegen 600K, Illumina 1M and Affymetrix 5.0 arrays is shown by vertical blue lines. M.Of.M.Cs., Massachusetts General Hospital offspring male case; W.Fa.M.Cn., Washington University father male control.

2. Figure 2: GRM receptor gene interaction networks affected in ADHD.