Why do some people get ADHD, while others do not? And how early in life or in the womb is the seed of ADHD sown?
Researchers have come closer to answering this question in a large
study, which has just been published in the journal Nature Genetics.
Together with national and international partners, the researchers have
studied more than six million genetic variants in 38,691 people with
ADHD and 186,843 people without ADHD. By this means it has been possible
to identify 27 genetic risk variants for the common neurodevelopmental
disorder.
The study is ground-breaking, inter alia because it finds more than
twice as many risk variants as previous studies have identified.
The term ”genetic variants” means specific variations in the
DNA code – in this case, variants which are observed more frequently in
people with ADHD than in people without the diagnosis. Variants in DNA
affect, for example, the degree to which a gene is expressed and
subsequently the amount of protein that is encoded by the gene.
By linking the genetic variants – i.e. the variations in DNA – to
specific genes, the researchers have gained new knowledge about which
tissues and cell types are particularly affected in individuals with
ADHD. The study is based on data from the Danish iPSYCH cohort, deCODE
Genetics in Iceland and the Psychiatric Genomics Consortium.
Subsequently, the researchers combined the results with existing data on
gene expression in different tissues, cell types and brain development
stages, and they discovered that genes involved in ADHD have a
particularly high level of expression in a wide range of brain tissues
and early in brain development – in fact already at the embryonic stage.
“This emphasises 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 the first author of
the study.
In addition, the researchers found that the genetics that increase the
risk of ADHD particularly affect genes that are expressed in neurons,
especially 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 the author.
ADHD is influenced by many common genetic variants, each of which increases the risk slightly, says the professor.
In fact, with the help of advanced statistical models, the researchers
have estimated that there are around 7,300 common genetic variants that
increase the risk of ADHD. It is particularly interesting that the vast
majority of these variants – 84-98 percent – also have an influence on
other mental disorders, e.g. autism, depression and schizophrenia.
It has previously been shown that risk variants for ADHD can affect a person’s cognitive abilities.
To investigate this further, the researchers analysed data from an
independent dataset, consisting of 4,973 people who had undergone
extensive neuro-cognitive tests. By using information from the new study
about which variants increase the risk of ADHD, they found in the
independent data set that an increased load of ADHD risk variants in the
genome of an individual is associated with reduced reading and
mathematical abilities, reduced attention and reduced short-term memory.
“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,” explains the author.
“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,” the author says.
Large international collaborations are crucial to identifying the
genetic causes of psychiatric diseases and neurodevelopmental disorders,
because to do so requires studies of tens or hundreds of thousands of
people with these conditions. Just as in the current ADHD study, there
are often 100 or more researchers involved, with different areas of
expertise, such as 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 the senior author of the study.
“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” the author says.
https://www.nature.com/articles/s41588-022-01285-8
