Genetic variants that increase the risk of ADHD identified

Why are some people diagnosed with ADHD while others are not? 

Genetic variants that increase the risk of ADHD identified
Professor Anders Børglum. Image Credit: Aarhus University (AU)

Aarhus University researchers have come pretty close to answering this question in a large study that was recently published in the journal Nature Genetics.

The scientists investigated more than six million genetic variants in 38,691 individuals with ADHD and 186,843 individuals without ADHD in collaboration with national and international partners. This method allowed researchers to find 27 genetic risk variants for the prevalent neurodevelopmental disorder.

Risk genes are expressed in the brain and neurons

The research is intriguing because it identifies over twice as many risk variants as earlier studies.

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

The scientists gained information as to which tissues and cell types are heavily impacted in ADHD patients by relating genetic variants—that is, DNA variations—to specific genes. Data from the Danish iPSYCH cohort, deCODE Genetics in Iceland, and the Psychiatric Genomics Consortium were used in the research.

After combining the findings with available data on gene expression in various tissues, cell types, and brain development stages, the scientists determined that genes involved in ADHD have an especially high level of expression in a broad range of brain tissues and early 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.”

Ditte Demontis, Study First Author and Professor, Department of Biomedicine, Aarhus University

Furthermore, the scientists discovered that the genetics that increases the risk of ADHD specifically affect 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.”

Ditte Demontis, Study First Author and Professor, Department of Biomedicine, Aarhus University

Associated with reduced concentration capacity and short-term memory

According to the professor, ADHD is impacted by several common genetic variants, each of which raises the risk slightly.

Using sophisticated statistical models, the scientists estimated that there are approximately 7,300 common genetic variants that increase the risk of ADHD. It is especially intriguing that the great majority of these variants—84 to 98%—also have an impact on other mental disorders, such as autism, depression, and schizophrenia.

It has been earlier demonstrated that ADHD risk variants can impair a person’s cognitive abilities.

To gain insight, the researchers examined data from an independent dataset of 4,973 individuals who had undergone 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 linked to diminished reading and mathematical abilities, decreased attention, and reduced short-term memory by using information from the new research 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 ADHD. This knowledge can be used as a starting point for further studies of the disease mechanisms and identification of new drug targets.”

Ditte Demontis, Study First Author and Professor, Department of Biomedicine, Aarhus University

Ditte Demontis emphasized the need to follow up on the study.

Ditte Demontis notes, “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.”

International cross-disciplinary collaboration is the way forward

Large global partnerships are vital for recognizing the genetic causes of psychiatric diseases and neurodevelopmental disorders since the research of tens or hundreds of thousands of people with these conditions is required. As in the present ADHD study, there are frequently 100 or more scientists involved, with expertise in genetics, psychology, psychiatry, molecular biology, epidemiology, bioinformatics, statistics, 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,” states Professor Anders Børglum of the Department of Biomedicine, Aarhus University, who is the last author of the study and one of the research directors of the Danish iPSYCH project.

Professor Anders Børglum concludes, “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.”

Source:
Journal reference:

Demontis, D., et al. (2023) Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics. doi.org/10.1038/s41588-022-01285-8.

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