How Do Genetic Factors Contribute to ADHD Risk?

What you need to know

• This large genome-wide association study identified 27 genetic regions associated with ADHD risk, including 21 new regions not found in previous studies.
• ADHD risk genes are highly expressed in the brain, especially the frontal cortex, and in several types of brain cells including dopamine neurons.
• There is substantial genetic overlap between ADHD and other psychiatric disorders like autism and depression.
• Common genetic variants associated with ADHD risk are linked to lower cognitive performance, especially in attention and executive function.

New insights into the genetics of ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that affects both children and adults. It is characterized by persistent inattention, hyperactivity, and impulsivity that interfere with daily functioning and development. While we know ADHD runs in families and has a strong genetic component, the specific genetic factors involved have been unclear.

This study represents the largest genetic investigation of ADHD to date, analyzing DNA from over 38,000 individuals with ADHD and 186,000 controls without ADHD. By looking for genetic variants that occur more frequently in those with ADHD compared to controls, the researchers identified 27 regions of the genome that contribute to ADHD risk. This doubles the number of known genetic risk factors for ADHD.

Linking genetic variants to genes and brain function

Identifying genetic variants associated with a disorder is just the first step. The researchers then used multiple approaches to connect these variants to specific genes and biological processes. Some key findings include:

• ADHD risk genes are highly expressed in the brain, particularly the frontal cortex. This aligns with the known role of the frontal cortex in attention, impulse control, and other executive functions that are often impaired in ADHD.

• Several types of brain cells showed enrichment for ADHD risk genes, including both excitatory and inhibitory neurons. There was a particularly strong signal in dopamine-producing neurons in the midbrain. This supports longstanding theories about the involvement of the dopamine system in ADHD.

• Genes involved in communication between neurons at synapses may play an important role. Several ADHD risk genes encode proteins that are key components of synapses.

• Some ADHD risk genes are active early in brain development, during fetal and early childhood periods. This suggests that alterations in early neurodevelopmental processes may increase ADHD risk.

Shared genetics with other disorders

The study found substantial genetic overlap between ADHD and other psychiatric and neurodevelopmental disorders. For example, many of the same genetic variants that increase risk for ADHD also influence risk for autism spectrum disorder, depression, and schizophrenia.

This genetic correlation helps explain why these conditions often co-occur in individuals or families. It suggests there may be some shared biological pathways that, when disrupted, can lead to multiple different psychiatric outcomes depending on other genetic and environmental factors.

The genetic overlap was particularly strong for depression, with over 90% of genetic variants influencing ADHD risk also affecting depression risk. However, the direction of effect is not always the same - some variants may increase risk for both disorders, while others may increase risk for one but be protective for the other.

Impact on cognitive function

To explore how ADHD genetic risk factors might impact the brain, the researchers looked at cognitive test performance in a sample of children and young adults. They calculated a polygenic score for each individual, essentially summing up their genetic risk for ADHD based on the variants identified in the main study.

Individuals with higher ADHD polygenic scores tended to perform worse on several cognitive measures, including:

• Overall cognitive ability (IQ)
• Attention
• Working memory
• Verbal reasoning
• Nonverbal reasoning
• Spatial reasoning

The strongest effects were seen for attention, aligning with the core symptoms of ADHD. These findings help validate the genetic discoveries by linking them to relevant cognitive processes. They also provide insight into the mechanisms by which genetic risk factors may lead to ADHD symptoms - by subtly altering cognitive functions like attention and executive control.

Implications for understanding ADHD

This study significantly advances our understanding of the genetic basis of ADHD. Key implications include:

• ADHD is highly polygenic, meaning it is influenced by many genetic variants (estimated at over 7,000) each having a small effect. This complex genetic architecture helps explain why it has been difficult to find consistent genetic associations in smaller previous studies.

• There is unlikely to be a single “ADHD gene” or a simple genetic test to diagnose ADHD. Rather, risk is conferred by a complex combination of many genetic variants interacting with environmental factors.

• The overlap in genetic influences between ADHD and other psychiatric disorders suggests there may be shared neurobiological pathways. This could potentially lead to treatment approaches that are effective across multiple conditions.

• The links between ADHD genetic risk and cognitive performance provide a potential bridge between genes and behavior. This may help researchers trace the pathways from genetic variation to changes in brain circuits to ADHD symptoms.

Conclusions

• This large-scale genetic study identified many new genetic risk factors for ADHD, substantially advancing our understanding of its biological basis.
• ADHD risk genes impact brain development and function, particularly in the frontal cortex and dopamine system.
• There is extensive genetic overlap between ADHD and other psychiatric disorders, suggesting some shared biology.
• Genetic risk for ADHD is associated with subtle impairments in cognitive function, especially attention and executive control.

While much work remains to fully unravel the complex genetics of ADHD, this study provides a wealth of new insights and directions for future research. Ultimately, a deeper understanding of the disorder’s genetic and neurobiological underpinnings may lead to improved diagnosis, treatment, and support for individuals with ADHD.