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Researchers have identified 27 genetic risk loci for attention-deficit hyperactivity disorder (ADHD) and provided a window into how it relates to other psychiatric conditions.

The genome-wide analyses revealed 21 new loci linked with the neurodevelopmental disorder and found that it was influenced by thousands of genetic variants.

The vast majority of these variants were shared with other psychiatric disorders, such as autism spectrum disorder and schizophrenia.

Many of the 76 ADHD potential risk genes identified in the Nature Genetics study were involved in early embryonic development of the brain, with common variants particularly expressed in the frontal cortex.

“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 researcher Ditte Demontis, a professor in the department of biomedicine at Aarhus University in Denmark.

ADHD is a neurodevelopmental disorder affecting around one in every 20 children, and persists into adulthood in two-thirds of cases.

Although there is a major genetic component, its complex genetic architecture makes it difficult to unravel the underlying biological causes.

To investigate further, researchers combined information from the newly extended Danish iPSYCH cohort, deCODE Genetics in Iceland and the Psychiatric Genomics Consortium.

Together, they comprised 38,691 people with ADHD and 186,843 without the condition. The genome-wide analyses identified 27 significant loci, 21 of which were novel.

The three loci most strongly associated with ADHD were on chromosome one, five and 11, with the latter identified as a new ADHD risk locus.

A transcriptome-wide association study led to the identification of 23 distinct genes whose expression levels differed significantly between individuals with ADHD and control participants.

ADHD-linked gene expression was associated with major brain-specific neuronal cell types, including both excitatory and inhibitory neurons.

In particular, there was a significant relationship between ADHD-associated genes and the dopaminergic midbrain 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,” said Demontis.

“Our results indicate that the imbalance in dopamine in the brains of people with ADHD is partly attributable to genetic risk factors.”

Almost all variants that influenced ADHD overlapped with educational attainment, with the vast majority (79%) linked with a decrease in this measure.

Indeed, common ADHD risk variants were associated with impairment in several other domains of cognitive abilities.

ADHD also significantly genetically correlated with obesity, smoking, insomnia, age at first birth and longevity.

In terms of other neurodevelopmental and psychiatric disorders, it was associated with autism spectrum disorder, schizophrenia, and cannabis use disorder.

Further modeling indicated that approximately 7,300 common genetic variants influence ADHD risk, with between 84 and 98 percent of these also estimated to influence the other psychiatric disorders.

“Our analyses revealed ADHD to be highly polygenic, influenced by thousands of variants, of which the vast majority also influence other psychiatric disorders with concordant or discordant effects,” the researchers report.

They add: “Overall, 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.”

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