Defects in brain signalling pathways behind ADHD
London: US researchers analysing genetic influences in attention deficit/hyperactivity disorder (ADHD) have found alterations in specific genes involved in important brain signalling pathways.
According to paediatric researchers at The Children’s Hospital of Philadelphia, the new study raises the possibility that drugs acting on those pathways might offer a new treatment option for patients with ADHD who have those gene variants.
“At least 10 percent of the ADHD patients in our sample have these particular genetic variants,” Hakon Hakonarson, the study leader, said.
“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,” he said.
ADHD is a common but complex neuropsychiatric disorder, estimated to occur in as many as 7 percent of school-age children and in a smaller percentage of adults.
There are different subtypes of ADHD, with symptoms such as short attention span, impulsive behaviour and excessive activity. Its causes are unknown, but it tends to run in families and is thought to be influenced by many interacting genes.
For the study, the researchers did whole-genome analyses of 1,000 children with ADHD recruited at The Children’s Hospital of Philadelphia, compared to 4,100 children without ADHD.
They searched for copy number variations (CNVs), which are deletions or duplications of DNA sequences. They then evaluated these initial findings in multiple independent cohorts that included nearly 2,500 cases with ADHD and 9,200 control subjects. All the study subjects were children of European ancestry.
Among those cohorts, the research team identified four genes with a significantly higher number of CNVs in children with ADHD. All the genes were members of the glutamate receptor gene family, with the strongest result in the gene GMR5. Glutamate is a neurotransmitter, a protein that transmits signals between neurons in the brain.
“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,” Hakonarson said.
“Our findings get to the cause of the ADHD symptoms in a subset of children with the disease,” he said.
Josephine Elia, co-author of the study, said that the fact that their study identified gene variants involved in glutamate signalling is consistent with studies in animal models, pharmacology and brain imaging showing that these pathways are crucial in a subset of ADHD cases.
“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,” she added.
The study has been recently published online in Nature Genetics.