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Heritability: mapping the path from genes to disorders

This post is also available in Dutch.

Many psychiatric and some neurological disorders run in the family. But if the cause is ‘in the genes’, where is it exactly? And why do we want to know?

We often hear that the risk of a certain disorder depends partially on your family history. If a disorder is highly prevalent among members of the same family tree, the disorder could be (partly) heritable. Members of that family could then pass on ‘risky’ pieces of DNA to their offspring. Those risky pieces of DNA are clues for scientists who want to understand how a disorder develops.

As you will see, there are cases in which scientists were able to track down the specific gene causing all the problems, whereas other cases are much more complex.

Huntington’s disease: a ‘simple’ genetic case

Huntington’s disease is a progressive brain disorder marked by loss of control over movements, as well as changes in personality and thinking. Sadly, there is no cure for this rare disease, which leads to premature death. Huntington’s fits our classic view of heritability found in high school textbooks. If a parent has this disorder, there is a 50% chance that it will be transmitted to the child.

With this knowledge, researchers went on to explore the DNA of families of people with Huntington’s. They found that the main culprit was a mutation in the HTT gene. If the mutated instead of the healthy gene was transmitted to the child, the child would ‘simply’ get the disease. By mimicking this mutated gene in rodents, researchers were able to learn more about the biology involved. The mutation leads to a malformation of a protein in the brain, ultimately causing a breakdown of certain brain cells.

ADHD: a ‘complex’ genetic case

Attention-deficit/hyperactivity disorder (ADHD) is another example of a disorder with high heritability. Because of this, researchers thought that ADHD would largely be in the genes, and that the newest and fastest techniques would be able to detect the DNA pieces that are ‘misbehaving’.

Unfortunately, this did not go as quickly as hoped. That is because ADHD is not about one or a few large genetic abnormalities that cause the condition. On the contrary, it is likely that the majority of people with ADHD have very ‘normal’ DNA.

Our DNA is largely the same as other people’s DNA, but here and there, it shows small variations. All variants that may contribute to ADHD are equally common, but a certain variant can slightly alter a bit of someone’s biology. This can increase the tendency for inattention and/or hyperactive or impulsive behaviour to occur.

The more of these ‘common risk variants’ someone has, the higher the chance that someone displays noticeable ADHD symptoms and experiences difficulties because of it. Researchers estimate that there are thousands of DNA variants with a small effect on ADHD symptoms, which makes the puzzle a lot more complex than with Huntington’s disease.

How can we find so many genes?

To find the thousands of genes involved in ADHD, researchers have to scan the whole DNA in one go with what we call a ‘genome-wide association study’ (GWAS). If we scan and compare the DNA of large groups of people with ADHD and without ADHD, we can detect the common variants that are more prevalent in people with ADHD.

The top image shows a Manhattan plot and the bottom image explains why we call it that.
A Manhattan plot is a typical result of a GWAS study. Horizontally in the image, all DNA locations are shown. If a certain location contains a genetic variant that is more common in people with the disorder, that variant shows up as a dot above the top line.
Top image source: Ikram et al. (2010), via Wikipedia (Creative Commons Attribution 2.5 License).
Bottom image source: Tommy Andreassen via Pixabay (Pixabay License).

In 2018, the first 12 genetic variants for ADHD were detected in a GWAS with a large, worldwide sample of almost 60,000 participants. Even though each variant only has a tiny effect, together they can give more insight into which biological processes increase the vulnerability for ADHD. Some of the genes that were found have a role in the communication between brain cells.

There is more to it than a load of genes…

It is important to note that a heritable vulnerability for ADHD does not mean that it is only the biology of the brain that decides if someone will display symptoms. This also holds for many other psychiatric disorders that have a complex contribution of genetic risk factors such as schizophrenia, mood and anxiety disorders. The brain operates in an environment full of events, social interactions, stressors, substances, etc. that interact with the biology. The ultimate puzzle of many psychiatric disorders is the complex interplay between biology and environment. Psychiatric genetics is still taking its first baby steps on the path from genes to disorders… but we are getting there, variant by variant.

Original language: English
Author: Sophie Akkermans (Guestblog)
Buddy: João Guimarães
Editor: Monica Wagner
Translator: Wessel Hieselaar
Editor Translation: Jill Naaijen

Top image source: Patrisia Novianti via Pixabay (Pixabay License).

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