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CNV Study Supports Role for Brain Signaling Gene Family in ADHD

NEW YORK (GenomeWeb News) – By comparing copy number variation patterns across the genomes of thousands of children with or without attention deficit hyperactivity disorder, a Children's Hospital of Philadelphia-led team has tracked down a gene family that is more frequently affected by CNVs in those with ADHD.

As they reported online in Nature Genetics yesterday, the researchers initially assessed genome-wide CNV data on more than 1,000 individuals with ADHD and 4,100 individuals without the condition. Based on CNV patterns in this discovery stage and in replication studies of nearly 12,000 more cases or controls, the team found an over-representation of CNVs affecting genes encoding metabotropic glutamate receptors that help transmit signals between neurons in the brain.

Moreover, their analysis of ADHD-associated CNV patterns in the context of gene interaction networks indicated that roughly 10 percent of ADHD cases involve copy number changes that alter genes that either interact with or belong to the GRM family.

"The genes involved affect neurotransmitter systems in the brain that have been implicated in ADHD," CHOP Center for Applied Genomics Director Hakon Hakonarson, the study's senior author, said in a statement, "and we now have a genetic explanation for this link that applies to a subset of children with the disorder."

Although the heritability of ADHD appears to be quite high, many different genes are thought to contribute to the condition, the study authors noted, and the genetic underpinnings for many cases remain unexplained.

"ADHD is a highly heterogeneous disorder, and separating out the different sub-groups of genetic mutations that these children have is very important," co-lead author Josephine Elia, a child psychiatrist affiliated with CHOP and the University of Pennsylvania School of Medicine, said in a statement.

In an effort to explore the potential contribution of copy number changes to ADHD, the researchers used Illumina's InfiniumII HumanHap550 BeadChip to genotype 1,013 children with ADHD and 4,105 unaffected controls, all of European descent. They were then able to glean CNV patterns across the genomes of the participants using genotype and signal intensity data.

"To identify CNVs associated with ADHD, we applied a segment-based approach for consecutive SNPs with more CNVs in cases than in controls," researchers explained. "The genomic span for consecutive SNPs delineates the shared CNV regions."

From CNV patterns in the discovery group and in almost 2,500 cases and more than 9,200 controls from additional replication cohorts of European ancestry, the team found that the four CNV regions that were most significantly associated with ADHD all encompassed metabotropic glutamate receptor or GRM genes.

Six individuals with ADHD had deletions affecting the metabotropic glutamate receptor gene GRM7 on chromosome 3 and eight had deletions affecting the GRM8 gene on chromosome 7 — copy number changes that were not found in controls tested for the discovery or replication phases of the study.

Meanwhile, 10 individuals with ADHD carried deletions involving the chromosome 11 gene GRM5, as did one child without the condition. Eight cases and two control individuals had duplications impacting GRM1 on chromosome 6.

By looking more closely at genetic data for parent-child trios, when available, researchers found that at least three of the GRM5 deletions had cropped up de novo and were not found in the parents of affected individuals.

Dozens of other genes that are known to interact with GRM genes also appeared more prone to be affected by CNVs in individuals with ADHD than in controls, based on the team's network analyses and CNV data for the discovery cohort.

And, the researchers added, the findings appear to be consistent with past ADHD studies hinting that some ADHD cases involve alterations in GRM family signaling. This so-called glutamatergic signaling, in turn, is thought to influence processes ranging from neuronal development to brain connectivity and communication across synapses.

"Taken together, our CNV analysis shows that the GRM gene family and genes interacting with it are enriched for CNVs in individuals with ADHD," the researchers wrote. "Several of these genes are crucial in the process of synaptic transmission, in neurogenesis, and in neuronal processes that may be defective in ADHD."

Though more research is needed, the investigators noted that their results so far suggest it might eventually be possible to treat a subset of ADHD cases by specifically targeting GRM genes.

"[E]nrichment of CNVs in genes within this molecular system that are associated with ADHD has suggested new susceptibility mechanisms and is likely to spur assessment of additional variations, including single base changes, and expression and functional assays to evaluate the biological effects of these CNVs," they concluded.

"Future work will determine whether clinical studies using selective GRM agonists as a potential treatment for ADHD are warranted in individuals with ADHD and variants in GRM genes," they said.

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