Researchers have identified 27 genetic variants associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD). The genetic variants affect genes overexpressed in numerous brain tissues and genes overrepresented among genes that are expressed during fetal brain development.
Researchers have taken another step in determining how ADHD develops, identifying 27 genetic variants in which tiny changes in the genetic code in or around genes are associated with an increased risk of ADHD.
According to a researcher involved in the study, the discovery suggests which brain tissues are involved in developing ADHD and how far back in life it originates.
“We found that variants associated with an increased risk of ADHD can be linked to genes that are overexpressed in many brain tissues. We also found that these genes are overrepresented among genes overexpressed during fetal brain development, which indicates that ADHD must partly originate there. Our results therefore demonstrate that the genetic risk component primarily affects the genes in the brain, which support the hypothesis that ADHD is a neurodevelopmental disorder,” explains Ditte Demontis, Professor, Department of Biomedicine, Aarhus University.
The research has been published in Nature Genetics.
Screening 225,000 people
The researchers performed a genome-wide association study meta-analysis on 38,691 individuals with ADHD and 186,843 controls.
The study was based on data from the iPSYCH cohort, deCODE Genetics and the Psychiatric Genomics Consortium.
The researchers used the data to search for differences in the genetic code among more than 6 million genetic variants between individuals with and without ADHD.
The study identified 27 genetic variants that are more frequent among individuals with ADHD than among controls.
“Each genetic variant is associated with a very small increased risk of developing ADHD. The overall genetic risk component comprises many genetic variants, and the more of these variants an individual has in their genome, the more the risk increases,” says Ditte Demontis.
The researchers used advanced statistical models to estimate that about 7,300 common genetic variants in the population influence the risk of developing ADHD.
“We only identified the tip of the iceberg, because many more variants are associated with ADHD. Each variant has a tiny influence, but having many variants overall can substantially affect the risk,” explains Ditte Demontis.
ADHD and other disorders share many genetic variants
The researchers also attempted to identify which genes are affected by the genetic variants.
Sometimes a variant is located in the middle of a gene, and then that gene is quite likely to be affected.
However, the variants are often outside the genes in the regulatory parts of the genome, and then researchers need to identify which genes are affected.
The researchers therefore linked their newly discovered genetic variants to other data sets, which helped them to track down which genes and cells are affected.
This part of the study showed that the vast majority of genetic variants associated with ADHD are among genes that are overexpressed in the brain compared with other tissues.
The genetic variants associated with ADHD are also more frequent among genes that are highly active in early brain development.
“Linking the genetic variants to the likely affected genes shows that ADHD is a neurodevelopmental disorder. We found that genetic ADHD risk variants are overrepresented in regulatory regions of the genome that affect genes expressed in neurons, and other analyses pointed especially at dopaminergic neurons. This is interesting because dopamine plays an important role in the reward responses in the brain and because a common ADHD medication works by increasing the levels of dopamine in various brain regions. Our results therefore indicate that genetic risk factors might affect the imbalance of dopamine in the brain of people with ADHD ,” says Ditte Demontis.
The researchers also found that 84–98% of the genetic variants associated with the risk of developing ADHD are also associated with the risk of developing other mental disorders, including schizophrenia, depression and autism.
“We have known for a long time that these disorders have significant genetic overlap and are often intertwined biologically. Our findings support this hypothesis,” explains Ditte Demontis.
Developing better drugs
According to Ditte Demontis, the fact that the genetic variants identified influence brain tissue and development is not surprising.
The research thereby also provides deeper insight into what and how the brain of people diagnosed with ADHD differ from those not having ADHD. This may identify a path for treating people with ADHD or other closely linked disorders in the future.
As researchers identify more genetic variants associated with ADHD, they can create a better polygenic risk score that can identify people’s personal risk of developing ADHD.
Ditte Demontis says that the intention is to make a diagnosis based only on genetic information. In general, polygenic risk scores are more likely a tool that can be implemented in the clinic to help screen individuals with ADHD (and other disorders) to identify those with particularly high genetic risk for other disorders, such as alcohol and cannabis use disorder, that often co-occur with ADHD.
“However, getting closer to the underlying biology, such as which tissues and cell types in the brain are affected in people with ADHD, is very important to understand the disorder better, to develop drugs or to reduce its symptoms in other ways,” she concludes.
“Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains,” has been published in Nature Genetics. In 2020, the Novo Nordisk Foundation awarded a grant to Ditte Demontis for the project Disentangling the Genetic Architecture Underlying Externalising Childhood Psychiatric Disorders and Comorbid Cannabis Use Disorder. She is also supported through the Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Cambridge, MA, USA. The Foundation has awarded several grants to the Danish National Biobank, used as a resource in the study.
