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Genome Wide Copy Number Variation Study Associates Metabotropic Glutamate Receptor Genes with Attention Deficit Hyperactivity Disorder, Nature Genetics, 44, 78-84. doi: 10.1038/ng.1013.(request a copy) (view article)

Introduction: ADHD is a common, heritable neuropsychiatric disorder of unknown etiology. -- Recently, we identified an enrichment of rare variants in genes involved in learning, behavior, synaptic transmission and CNS development in autism, suggesting that rare inherited structural variants could also play a role in the etiology of ADHD, a related neuropsychiatric disorder.

Methods: We performed a whole-genome copy number variant (CNV) study in a cohort of 1,013 ADHD cases & 4,105 healthy children of European ancestry who were genotyped with 550,000 SNP markers. Positive findings were evaluated in multiple independent cohorts, totaling 2,493 ADHD cases and 9,222 controls of European ancestry.


1/ CNVs impacting metabotropic Glutamate receptor (mGluR) genes were significantly enriched across all independent cohorts (P = 2.1 x 10-9).

2/ Among them, deletions in GRM5 (Glutamate receptor, metabotropic 5) occurred in 9 cases across 3 independent cohorts and in only one control subject (P = 5.95 x 10-6).

3/ In addition, deletions in GRM7 occurred in 6 cases & GRM8 in 8 cases, both with a control frequency of zero.

4/ GRM1 was duplicated in 8 cases, a frequency notably enriched above Cs.

5/ Observed variants were experimentally validated using quantitative PCR.

Discussion: Taken together, we have identified several rare recurrent CNVs that are over-represented in multiple independent ADHD cohorts & impact genes involved in Glu neurotransmission, an important-mediator for the developing brain & normal brain function. These results suggest that variations involving Glu gene networks of the brain contribute to the genetic susceptibility to ADHD.

Background: a) mGluRs are a class of G-protein-coupled receptors that possess a 7 trans-membrane region involved in the modulation of excitatory synaptic transmission. There are 3 receptor groups based on sequence homology, putative signal transduction mechanisms, and pharmacologic properties. GRM5 & GRM1 are members of Group I expressed particularly in the basal ganglia and cerebellum, relevant brain areas for ADHD. These receptors have been shown to activate phospholipase C & it has been postulated they may play a role in addiction, anxiety and behavioral disorders. GRM7 & GRM8 are members of Group III which is linked to the inhibition of the cyclic AMP cascade. GRM7 has been linked with anxiety and is the most highly conserved of all mGluR subtypes across different mammalian species.

b) 8 other loci were associated with ADHD, 5 of which directly impact genes (Table 1B). Among these are the following genes all of which have intriguing biology with respect to ADHD. DPP6 is a gene previously associated with Amyotrophic Lateral Sclerosis (ALS) in a genome wide association study. CNVs impacting DPP6 have been reported in relation with autism. DPP6 and CTNNA2 (although our association does not directly impact CTNNA2) have been implicated by earlier ADHD SNP genotype GWAS. NLN is an interesting candidate responsible for metabolic inactivation of neural peptides, such as Neuropeptide Y (NPY) which has previously been implicated in ADHD ( Oades et al., 1998 ).

Support: NIH.