Although conditions such as attention-deficit/hyperactivity disorder (ADHD) or schizophrenia only appear later in life, a new study shows that the seeds are often sown during pregnancy. The researchers suggest that screening for genetic predisposition could enable intervention long before medication is needed.
When people develop symptoms of neurodevelopmental disorders such as ADHD, autism, bipolar disorder or schizophrenia, the processes behind them have often been unfolding for many years.
In fact, they can originate very early in fetal development.
This has been shown by a new study in which researchers for the first time linked vast quantities of single-cell data on brain development directly to known genetic risk variants for mental illness.
The study shows that neurodevelopmental disorders can originate as early as the first trimester of pregnancy and in the very earliest stages of brain development.
It also identifies which types of cells are most likely to be implicated when people later develop mental illness.
“We already know what can genetically lead to an increased risk of developing neurodevelopmental disorders. With this study, we show when in fetal development this genetic risk arises and in which cells,” explains a researcher behind the study, Konstantin Khodosevich, Professor at the Biotech Research & Innovation Centre at the University of Copenhagen, Denmark.
The research has been published in Biological Psychiatry Global Open Science.
A vast dataset maps the brain’s earliest vulnerabilities
Konstantin Khodosevich and his colleagues compiled data from the scientific literature to create the largest dataset of its kind for studying neurodevelopmental disorders.
The data are based on single-cell RNA sequencing – a method that enables researchers to read the activity in each individual brain cell and see precisely which genes are switched on and which are switched off.
In total, the researchers included data from more than 1 million individual cells.
The researchers compared these data with evidence that 127 genetic variants – variations in genes between humans – are associated with an increased risk of developing numerous neurodevelopmental disorders, including ADHD, autism, epilepsy, schizophrenia and bipolar disorder.
These 127 variants are copy number variations. This is equivalent to a chapter in a book sometimes being printed twice – or omitted entirely. Such small differences in DNA can strongly affect how the brain is constructed.
In many previous studies, copy number variations have been linked to an increased risk of developing neurodevelopmental disorders among people with either more or fewer copies of these parts of the genome.
The question has been when this genetic variation manifests – and in which cells.
Activity of disease genes is already visible in the first months of pregnancy
The researchers found that genetic risk markers – the small signals in the genome that indicate where the risk lies – are especially active in the very early development of the brain, already in the first trimester of pregnancy.
This is where the foundation is laid for the later development of neurodevelopmental disorders and applied to all those studied.
Although the differences in genes cannot be detected at birth, the child carries them as a hidden inheritance that only later – in childhood or adolescence – can unfold as mental symptoms.
Some people develop ADHD, and others can develop much more serious mental illness.
The researchers also identified which cells are most often involved when brain development goes wrong in the first trimester of pregnancy.
Two main types stood out: neural stem cells — the building blocks that create new cells – and neurons, which become the electrical wires that connect the brain’s networks.
“This suggests that neurodevelopmental disorders may develop through different pathways. Some genetic disorders may cause problems at the stem cell level, and others affect neurons after they have developed. This knowledge is relevant because we can use it to think about possible treatments,” says Konstantin Khodosevich.
Early knowledge may prevent disease
For the researchers, the results raise hopes that new knowledge about the earliest stages of brain development may be used to prevent mental disorders before they emerge.
He emphasises that he is not a doctor, but there can be many advantages to knowing that neurodevelopmental disorders will develop before they do.
According to Konstantin Khodosevich, the results open a window of opportunity to intervene before the disorders emerge – and perhaps prevent people from having many years of suffering.
This can be done with medicine, but children and adolescents can also benefit from coping strategies other than medicine so that they can better manage the disorders when they appear.
“The focus is not screening everyone for the predisposition to develop neurodevelopmental disorders, but monitoring young people with a family history of mental illness more closely may make sense – similar to children in families with diabetes or heart disease – and exploring opportunities for early intervention. If we can intervene early – especially among children from families at risk – we may be able to change their life-course for good and prevent the disorders from ever breaking out,” concludes Konstantin Khodosevich.
