What Should the Clinician Know About ADHD Genetics?

The phrase “genetic variants” refers to specific mutations in the DNA code that are more common in individuals with ADHD than in those without the diagnosis. Variations in DNA, for example, impact the extent to which a gene is expressed and, as a result, the amount of protein encoded by the gene.

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The researchers got a fresh understanding of which organs and cell types are most affected in ADHD patients by tying genetic variants, that is, DNA changes, to specific genes. The research is based on data from the Danish iPSYCH cohort, Iceland’s deCODE Genetics, and the Psychiatric Genomics Consortium.

After combining the findings with existing data on gene expression in various tissues, cell types, and brain development stages, the researchers have found that genetic factors in ADHD have especially high expression levels in a wide range of brain tissues and slightly earlier in brain development—in fact, even at the embryonic stage.

“This emphasizes that ADHD should be seen as a brain developmental disorder, and that this is most likely influenced by genes that have a major impact on the brain’s early development,” says Professor Ditte Demontis of the Department of Biomedicine at Aarhus University, who is the first author of the study.

Furthermore, the researchers discovered that the genotypes that enhance the risk of ADHD specifically influence genes expressed in neurons, particularly dopaminergic neurons.

“This is interesting because dopamine plays a role in relation to the reward response in the brain and because a frequently used form of ADHD medicine works by increasing the concentration of dopamine in different brain regions. Our results indicate that the imbalance in dopamine in the brains of people with ADHD is partly attributable to genetic risk factors,” says Ditte Demontis.

Decreased Concentration and Short-term Memory

According to the professor, ADHD is influenced by numerous common genetic variations, each of which increases the risk somewhat.

Indeed, using complex statistical models, the researchers determined that there are approximately 7,300 common genetic variations that raise the risk of ADHD. It’s also intriguing since the vast majority of these polymorphisms (84-98 percent) also have an impact on other mental diseases, such as autism, depression, and schizophrenia.

It has already been demonstrated that ADHD risk variations can impair a person’s cognitive ability.

To dig deeper, the researchers examined data from an independent dataset of 4,973 individuals who had completed extensive neuro-cognitive tests. They discovered in an independent data set that an increased load of ADHD risk variants in an individual’s genome is associated with reduced reading and mathematical abilities, reduced attention, and reduced short-term memory by using data from the new study about which variants increase the risk of ADHD.

“The results increase our knowledge of the biological mechanisms underlying ADHD, and they point to specific genes, tissues, and cell types involved in the disorder.” “This knowledge can be used as a starting point for further research into disease mechanisms and the identification of new drug targets,” Ditte Demontis explains.

She emphasizes that the study must be followed up on.
“We have only mapped a small fraction of the common variants that influence ADHD—just 27 of the 7,300 that potentially exist. So there is a need for larger genetic studies,” she says.

International Collaboration Across Disciplines is the Way to Go

Large multinational collaborations are critical for uncovering the genetic origins of psychiatric diseases and neurodevelopmental problems since investigations of tens or hundreds of thousands of people with these conditions are required. As in the current ADHD study, there are frequently 100 or more experts involved, with skills in genetics, psychiatry, psychology, epidemiology, molecular biology, statistics, bioinformatics, and computer science.

“In order to understand more of the genetic and biological mechanisms, it is important to have even larger studies, involving more people with ADHD,” says Professor Anders Borglum of the Department of Biomedicine, Aarhus University, who is the last author of the study and one of the research directors of the Danish psych project.

“But it is also important to undertake studies that focus on identifying how the genetic risk variants perturb biological processes in the brain cells (the neurons), and their way of joining up and communicating with each other in the brain. For the latter, both brain cells and early developmental stages of the brain, so-called mini-brains or brain organoids, are currently being examined,” he says.

Reference :

1. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains – (https:www.medrxiv.org/content/10.1101/2022.02.14.22270780v1)

Source: Medindia