Editors' ChoiceGenetic Epidemiology

Genomic and Attention Deficits

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Science Translational Medicine  01 Feb 2012:
Vol. 4, Issue 119, pp. 119ec17
DOI: 10.1126/scitranslmed.3003773

Dissecting attention deficit hyperactivity disorder (ADHD) has required sustained efforts by scientists who use creative combinations of innovative technologies. Indeed, gene hunters have made strides in understanding ADHD by combining two cutting-edge analytical methods for use in genomic studies. Previous genome-wide association studies of ADHD patients and control subjects examined single-nucleotide polymorphisms but failed to reveal the genetic underpinnings of this highly heritable but complex condition. Now, Elia et al. focus instead on a different kind of genetic aberration called copy number variations (CNV)—deletions or duplications of multiple adjacent nucleotides in a gene region—to unearth genetic contributions to ADHD.

In a study of several thousand children with ADHD and healthy controls, CNVs in metabotropic glutamate receptor genes (GRMs), which encode a class of receptors for the neurotransmitter glutamate, appeared either solely or at a far greater frequency in the genomes of ADHD subjects as compared with controls. Nevertheless, CNVs were rare, with 32 ADHD cases (0.9%) and 3 controls (0.02%) accumulating deletions in three GRMs and a duplication in a fourth GRM.

To evaluate the effects of mutations in GRM-related genes—those that encode proteins, other than glutamate receptors—that might also play a role in glutamatergic neurotransmission, the investigators turned to network analysis. This approach allowed for the identification of genes with known functional links to GRM, and cases were three times as likely as controls to have a CNV in one of these GRM-related genes. Whereas GRM CNVs were extremely rare, ~10% of ADHD cases showed a frequency of CNV mutations in GRM-related genes that was greater than that of control subjects. Together, these results suggest the potential for a new treatment target for ADHD.

Glutamate receptors are involved in regulation of excitatory synaptic transmission and are thought to play a role in neuropsychological conditions such as addiction and anxiety. The functional effects of the deletions and duplications in the GRM genes and those in the network remain to be elucidated. These effects might be expected to differ by the specific location or size of the CNV, making predictions of ADHD phenotype severity or treatment response challenging. Beyond the implications for ADHD treatment, this study illustrates the utility of combining CNV and network analyses for discovering how genetic variation affects complex phenotypes.

J. Elia et al., Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat. Genet. 44, 78–84 (2012). [Abstract]

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