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ADHD is a neurodevelopmental disorder with a high heritability, in which the genetic component consists of thousands of genetic variants. Most variants only slightly increase the likelihood of receiving the diagnosis.

Now an international study led by researchers from iPSYCH at Aarhus University has shown that rare high-effect genetic variants also play an important role.

The study has been published in Nature, and the researchers have found a markedly increased likelihood of developing ADHD among individuals carrying rare variants in three genes – MAP1A, ANO8 and ANK2 – in some cases by up to 15 times.

These genetic variants are very rare, but when present, the study shows that they strongly affect genes expressed in the brain’s nerve cells. In individuals carrying these variants, the development and communication between nerve cells may therefore be disrupted, which can result in ADHD.

“We can now, for the first time, point to very specific genes in which rare variants confer a high predisposition to developing ADHD,” says Professor Anders Børglum from the Department of Biomedicine at Aarhus University, who is the senior author of the study.

“The identified variants very likely have a highly damaging effect on the genes, and they show us precisely which genes and fundamental biological mechanisms may be affected,” he continues.

Affects the brain from foetal life into adulthood

By combining genetic data with data on how genes are expressed in different cell types in the brain, the researchers have shown that the rare variants involved in ADHD particularly affect the function of dopaminergic and GABAergic neurons. These cell types help regulate attention, impulse control and motivation.

The effects can be traced as early as foetal life and continue into adulthood.

“Our findings support that disturbances in brain development and function are central to the development of ADHD,” explains Ditte Demontis, Professor at the Department of Biomedicine at Aarhus University and first author of the study.

“We have also analysed which proteins interact with the proteins encoded by the three identified ADHD genes, and we have identified a larger protein network that also plays a role in other neurodevelopmental disorders - including autism and schizophrenia. This provides insight into the biological links across several psychiatric diagnoses,” she says.

Implications for IQ, education and employment

The rare genetic variants not only affect who develops ADHD but also influence how individuals with ADHD fare in the education system and labour market.

By linking genetic data to Danish registry data, the researchers found that individuals with ADHD who carry the rare variants have, on average, lower educational attainment and socioeconomic status than those without the variants.

Among adults with ADHD, an average reduction in IQ score of around 2.25 points was observed for each rare high-risk variant they carry.

“This suggests that individuals generally face greater cognitive challenges if they have ADHD due to these rare genetic variants, which may have educational and occupational consequences,” says Jinjie Duan, postdoctoral researcher in the Aarhus group and co-first author of the paper.

“This is only the beginning”

The findings broaden our understanding of the biological underpinnings of ADHD and may lay the groundwork for future treatment.

“The study provides a new and concrete direction for mapping the biological mechanisms involved in ADHD, because we now know causal genes with high-effect variants. They give us insight into some of the fundamental biological processes, which can guide the design of deeper mechanistic studies - for example, to identify new therapeutic targets,” says Anders Børglum.

Jinjie Duan adds:

“Yes, and we are only at the beginning of uncovering these rare high-effect variants. Our calculations show that there are many more rare causal variants that can be identified in even larger studies. In the current study, we can already point to 17 additional genes with rare variants that are very likely to be causal.”

Contact

Professor 
Aarhus University, Department of Biomedicine
Phone: 60202720
Email: anders@biomed.au.dk

Professor Ditte Demontis
Aarhus University, Department of Biomedicine
Phone: 28539746
Email: ditte@biomed.au.dk

Postdoc 
Aarhus University, Department of Biomedicine
Phone: 50160065
Email: jjduan@biomed.au.dk