CNV study finds alterations in GRM genes and signaling network in 10% of pediatric cases.

Scientists have identified changes in four different metabotropic glutamate receptor (GRM) genes in pediatric attention deficit hyperactivity disorder (ADHD). Analysis of data from a whole-genome copy number variation (CNV) study in some 1,000 ADHD patients identified deletions or duplications in GRM genes in a number of cases, but not in controls. These genetic changes were confirmed in a replication study in multiple independent cohorts involving another 2,500 patients.

The study, led by Hakon Hakonarson, M.D., director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia (CHOP), also found through gene network analysis that genes interacting with the GRM family members were enriched for CNVs in about 10% of cases. The researchers claim the data support emerging evidence for glutamatergic involvement in ADHD from other fields of research. Their findings are reported in Nature Genetics in a paper titled “Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.”

To look for genetic anomalies correlated with ADHD, the team carried out whole genome CNV analysis on a discovery cohort compiled and genotyped by the Children’s Hospital of Philadelphia. The cohort included 1,013 ADHD cases of European descent, and 4,105 healthy children of European ancestry, aged 6–18 years. Statistically significant findings were then evaluated using matched platforms in multiple additional cohorts, including a total of 2,493 cases with ADHD and 9,222 controls of European ancestry.

Data from the initial CHOP cohort highlighted 10 previously unreported CNV regions (CNVRs) that were present in multiple cases but not in con­trols, and two CNVRs that had a higher frequency in cases than in controls. Three of the CNVRs included deletions in the metabotropic glutamate receptor genes GRM5, GRM8, and GRM7, and one was a duplication in GRM1. The team also identified the previously reported duplication in 16p13.11 in three cases and no controls. All CNVRs were validated using quantitative RT-PCR.

When the putative ADHD-related CNVRs were assessed in the replication cohort, the four GRM alterations were again found to be enriched in the ADHD cases. Additional GRM2 and GRM6 deletions were found in single cases within the discovery and replication cohorts, but not in any of the controls. Significantly, the investigators identified numerous genes that interacted with GRM genes (i.e., not including the GRM genes themselves) enriched for CNVs in cases, compared with controls. In fact there was a threefold enrichment of the GRM network CNVs in individuals with ADHD, they write. This finding excluded large CNVs spanning multiple genes.

“Extended studies identified over 200 genes interacting with glutamate receptors that were collectively affected by CNVs, sug­gesting that up to 10% of individuals with ADHD may be enriched for GRM network variants,” they suggest.

GRMs are GPCRs involved in the modula­tion of excitatory synaptic transmission, the authors explain. These are classified into three groups based on sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group 1 members GRM5 and GRM1 are expressed in the basal ganglia and cerebellum, and research has indicated they may play roles in addiction, anxiety, and behavioral disorders. The group 3 receptors GRM7 and GRM8 are inhibitors of the cyclic AMP cascade, and GRM7, which is the most highly conserved GRM across a range of species, has been linked with anxiety.

Prior GWAS, linkage, magnetic resosonance spectroscopy, and animal model studies have provided some evidence for glutamatergic involvement in ADHD, the team notes, and increased concentrations of glutamate have been reported in the neurometabolism of ADHD brains, “which is consistent with altered glutamate transmission.” Moreover, within the cohorts assessed by the CHOP researchers, a number of ADHD patients with GRM deletions exhibited comorbid symptoms such as social avoidance, obsessive compulsive syndrome, anxiety, oppositional defiant disorder, and minor depression. 

Importantly, the GRM CNVs associated with ADHD confer large effect sizes, the team stresses. “Based on loci that are significant individ­ually, 3.66% of the cases with ADHD have the newly discovered CNVs, and this number increases to 9.94% when genes interacting with GRM genes are included. Major hubs of the network include TNIK50, GNAQ51, and CALM.”

Members of the GMR gene family, along with the genes they interact with, are involved in nerve transmission, the formation of neurons, and interconnections in the brain, Dr. Hakonarson states. “So the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD.”

The authors say 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. “ADHD is a highly heterogenous disorder, and separating out the different subgroups of genetic mutations that these children have is very important,” adds co-first author Josephine Elia, M.D. “This research will allow new therapies to be developed that are tailored to treating underlying cuases of ADHD. This is another step toward individualizing treatment to a child’s genetic profile.”

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