Four gene variants, all members of the glutamate receptor gene family, appear to be involved in vital brain signaling pathways in a sub-set of children with ADHD (attention deficit hyperactivity disorder), researchers from the Center for Applied Genomics at The Children’s Hospital of Philadelphia reported in the journal Nature Genetics. The authors add that their findings could help create drugs that target those pathways, offering potential therapies for ADHD patients with those specific gene variants. There are an estimated half-a-million American children with ADHD and these gene variants.

Study leader Hakon Hakonarson, M.D., Ph.D., said:

“At least 10 percent of the ADHD patients in our sample have these particular genetic variants. The genes involved affect neurotransmitter systems in the brain that have been implicated in ADHD, and we now have a genetic explanation for this link that applies to a subset of children with the disorder.”

ADHD, which is thought to affect about 7% of kids of school age and a smaller percentage of adults, is a complex neuropsychiatric disorder. ADHD has several subtypes, with varying symptoms that may include short attention span, impulsivity, and overactivity.

ADHD tends to run in families, nobody is sure what causes it – scientists and experts believe it is mainly caused by many genes which interact in certain ways. Although drugs are frequently prescribed for ADHD, they do not always work, especially if symptoms are severe.

The researchers carried out a study involving 1,000 kids with ADHD from a database at the Children’s Hospital of Philadelphia; they were compared with 4,100 others of the same age who did not have ADHD (controls). They did whole-genome analyses of all of them.

The scientists were looking for CNVs (copy number variations) – duplications or deletions of DNA sequences. They then compared these preliminary findings with various cohorts, made up of 2,500 kids with and 9,200 without ADHD. All the children where Caucasian.

They identified four genes with a considerably greater number of CNVs in the ADHD children. They were all glutamate receptor (GMR) genes. The one with the strongest result was gene GMR5.

Glutamate is an amino acid, one of the 20 AAa used to make all of the proteins in our body, it transmits signals between brain neurons – it is a neurotransmitter.

Hakonarson said:

“Members of the GMR gene family, along with genes they interact with, affect nerve transmission, the formation of neurons, and interconnections in the brain, 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. Our findings get to the cause of the ADHD symptoms in a subset of children with the disease.”

Co-first author Josephine Elia, M.D., said:

“ADHD is a highly heterogeneous disorder, and separating out the different subgroups of genetic mutations that these children have is very important.”

Dr. Elia, an ADHD expert, explains that thousands of genes may be involved in ADHD risk. However, finding a gene family which might be a major contributory factor in 10% of ADHD cases is a major breakthrough. 5.2 million children in the United States have been diagnosed with ADHD (overall), says the CDC (Centers for Disease Control and Prevention).

Their findings are consistent with those done with animal models, brain imaging studies and other investigations, Elia wrote, showing that these pathways play a vital role in certain types of ADHD cases.

Dr. Elia explained:

“This research will allow new therapies to be developed that are tailored to treating underlying causes of ADHD. This is another step toward individualizing treatment to a child’s genetic profile.”

Hakonarson believes his team’s findings will trigger further research and subsequent discoveries of ADHD-related genes along the GMR signaling pathways. According to current research, carefully selected GRM agonists could be used in human studies to determine whether they might have potential as therapies for ADHD patients with particular CNVs. Preclinical studies will need to be carried out first on candidate medications.

Written by Christian Nordqvist