Probable Risk Genes Linked to ADHD in Large Study
This international genome-wide study of ADHD — the largest to date — identified 27 genetic risk variants that influence ADHD and shed light on the genetic underpinnings of ADHD and its comorbidities.
February 16, 2023
Researchers have “refined the genetic architecture of ADHD” after identifying 27 variations in genetic code that are most present in people with the attention deficit hyperactivity disorder. A Danish-led international genome-wide association study (GWAS) published in Nature highlighted these and 76 probable risk genes — including “brain-expressed genes” involved in development and genes known to influence other psychiatric disorders. 1
The study identified 27 ADHD risk loci, or locations of a gene or mutation on a chromosome. Researchers then linked these loci to 76 ADHD risk genes. They found that many of the genes thought to influence ADHD also influence early embryonic brain development.
“This emphasizes that ADHD should be seen as a brain developmental disorder, and that [ADHD] is most likely influenced by genes that have a major impact on the brain’s early development,” said Ditte Demontis, one of the study’s authors and a professor at Aarhus University.
Researchers estimated that up to 7,300 common genetic variants influence ADHD, highlighting its polygenicity. They observed that common variants were often found in genes expressed in the frontal cortex, which is responsible for attention and working memory, and in genes expressed in midbrain dopaminergic neurons that control voluntary movement and reward processing.
“There was a time about 30 years ago when many scientists — and the general public — thought that… we would find the [one] gene for ADHD, bipolar disorder, autism, and so on,” said Joel Nigg, Ph.D., in a recent ADDitude webinar. “That is clearly wrong. We now know after 25 to 30 years of extensive genetic research that lots of genes are involved in these conditions; there’s lots of overlap and genetic correlations. And [we know] that genes don’t explain the whole story for any of these conditions, despite some fairly substantial genetic influence in all of them.”
According to the study, 84% to 98% of common variants tied to ADHD seemed to influence other psychiatric disorders including autism spectrum disorder, depression, and schizophrenia. This correlates with the high rate of comorbidity seen among ADHD patients.
“As many as 80% of adults with ADHD have at least one co-existing psychiatric disorder, while approximately 60% of children with ADHD have at least one co-occurring condition,” wrote Theresa Cerulli, M.D., in an ADDitude article about complex ADHD.
The considerable genetic overlap found in the current study helps to explain the frequency of ADHD comorbidities.
“The presence of co-occurring conditions almost always muddles the diagnosis, treatment, and prognosis of ADHD,” Cerulli wrote. “ADHD and comorbidities may also influence the presentation and severity of one another, which can complicate the detection and treatment of symptoms.
This GWAS meta-analysis of ADHD is the largest to date. Researchers analyzed twice as many ADHD cases and identified more than double the number of ADHD-associated loci compared to a 2019 GWAS. 2 That study helped establish the role of common variants in ADHD; the current study is an updated GWAS meta-analysis.
“The results advance our understanding of the underlying biology of ADHD and reveal new aspects of the polygenic architecture of ADHD, its relationship with other phenotypes and its impact on cognitive domains,” wrote the researchers.
The study sampled 186,843 people with ADHD, 38,691 controls, and analyzed data on over 6 million variants.
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1Demontis, D., Walters, G. B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T. T., … Børglum, A. D. (2023). Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics, 55(2), 198–208. doi: 10.1038/s41588-022-01285-8
2 Demontis, D., Walters, R.K., Martin, J. et al. (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet 51, 63–75. https://doi.org/10.1038/s41588-018-0269-7
