Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity and impulsivity. It is estimated to affect around 5% of children and 2.5% of adults worldwide. While the exact causes of ADHD are unknown, research suggests that genetics play a major role. Studies of twins indicate that ADHD is one of the most heritable psychiatric disorders, with estimated heritability around 70-80%. This means that differences in genes likely account for over two-thirds of the risk for developing ADHD. Identifying specific genes involved in ADHD is an important step towards better understanding the biology of this disorder.
The Role of Genetics in ADHD
There is strong and consistent evidence from multiple family, twin and adoption studies that ADHD has a very high heritability. This means that much of the differences between individuals in terms of their risk for developing ADHD can be attributed to differences in their genetic makeup. Some key findings supporting the genetic basis of ADHD include:
– High concordance rates in identical (monozygotic) twins. If one identical twin has ADHD, the other twin has around a 70-90% chance of also having ADHD. This is much higher than the around 30-40% concordance seen in fraternal (dizygotic) twins.
– Higher risk of ADHD among biological relatives. The parents and siblings of a child with ADHD are several times more likely to also have ADHD compared to the general population.
– Increased risk of ADHD even when a child is adopted away at birth from a biological parent with ADHD. Biological relatives have a higher risk regardless of environmental exposures.
Overall, behavioral genetics research powerfully points to inherited genetic variations as being responsible for much of the neurological and cognitive differences that manifest as ADHD. However, ADHD is considered a complex polygenic disorder. This means that many different genes, perhaps hundreds or thousands, each make small contributions to the overall inherited risk. Identifying these specific risk genes has been challenging.
Candidate Genes Identified in ADHD
Although ADHD is highly heritable, identifying the specific genes involved has been difficult. Most cases of ADHD likely result from the combined small effects of variations in many different genes, rather than mutations in a single gene. However, researchers have been able to identify certain candidate genes that may contribute to ADHD risk. Some of the most promising genes implicated include:
DAT1
The dopamine active transporter 1 (DAT1) gene codes for a protein that regulates dopamine signaling in the brain. Dopamine is a neurotransmitter involved in motivation, reward and movement that is thought to be dysregulated in ADHD. Variants in DAT1 may affect dopamine reuptake and are linked to inattentive and hyperactive/impulsive symptoms.
DRD4
The dopamine receptor D4 (DRD4) gene codes for a dopamine receptor in the brain. Variations in DRD4 have been associated with ADHD behaviors as well as responsiveness to medications that target dopamine signaling. The DRD4 7-repeat allele has been most strongly linked to inattentive symptoms of ADHD.
DRD5
Another dopamine receptor gene called dopamine receptor D5 (DRD5) has also been associated with increased ADHD risk and severity in some studies. A particular deletion variant of DRD5 has been linked to hyperactive and impulsive behaviors in ADHD.
5-HTT
The serotonin transporter gene SLC6A4 (also known as 5-HTT) is important for regulation of the neurotransmitter serotonin. Variants have been linked to inattentive and hyperactive/impulsive traits. Serotonin modulates important brain functions including mood, motivation, sleep and impulse control.
HTR1B
The serotonin receptor gene HTR1B codes for a receptor that serotonin binds to in the brain. Certain variations have been associated with comorbid aggressive and antisocial behaviors in individuals with ADHD.
Rare Genetic Mutations
While the genes described above may contribute small effects to ADHD risk, researchers have also identified some rare mutations that have large effects on risk in a small number of cases. These mutations likely account for <1% of all ADHD but provide insight into biological pathways involved.
Some rare variants linked to ADHD include:
CNTN6
The contactin 6 (CNTN6) gene codes for a protein important in formation of brain circuits. Deletions and mutations of CNTN6 have been associated with developmental delay, intellectual disability and features of ADHD.
FOXP2
The forkhead box protein P2 (FOXP2) gene is involved in development of language and speech areas of the brain. Disruptions in FOXP2 have been linked to a rare form of severe speech and language disorder, and mutations have also been associated with ADHD symptoms.
SHANK3
The SHANK3 gene codes for a scaffolding protein at synapses in the brain. Mutations have been linked to autism spectrum disorder and a small number of patients with ADHD-like features.
While each of these mutations individually accounts for very few cases, they point to biological pathways like neural connectivity and development that may be disrupted in ADHD.
Studies of Copy Number Variants
In addition to mutations in single genes, researchers have also found that larger chromosomal deletions and duplications called copy number variants (CNVs) may play a role in ADHD. Rare CNVs have been identified that increase risk for ADHD and related neurodevelopmental conditions like autism spectrum disorder. Key CNV regions implicated in ADHD include deletions/duplications on chromosome 16p13 and 17p12.
Some of the deleted or duplicated genes in these regions include:
16p13
– NDE1 – involved in neuron development
– NTAN1 – involved in dopamine signaling
17p12
– RAI1 – involved in neural development and function
– PEMT – involved in acetylcholine signaling
Though individually rare, copy number variants appear to contribute significantly to ADHD risk in a small proportion of cases. The genes impacted highlight neurodevelopmental processes relevant to ADHD.
Gene Pathways Involved in ADHD
Although the specific risk genes are not fully characterized, research does point to some key biological pathways that are likely disrupted in ADHD:
Dopamine Signaling
Genes involved in dopamine signaling, like DAT1, DRD4 and DRD5, are some of the most consistently associated with ADHD. Since dopamine is critical for motivation, focus and motor control, disruptions likely alter activity and impulse control.
Serotonin Signaling
Serotonin system genes like 5-HTT and HTR1B also modulate mood, attention and behavior. Serotonin may interact with dopamine pathways as well.
Synaptic Plasticity
Rare mutations in genes like SHANK3 involved in synapse formation and plasticity highlight the importance of intact connectivity. Problems with neural wiring likely alter development of key brain networks.
Neurodevelopment
Genes involved in neurodevelopment like CNTN6 and FOXP2 suggest ADHD may result from alterations to brain growth and maturation. Atypical brain development likely underlies symptoms emerging in childhood.
Gene-Environment Interactions
While genetics are strongly implicated, potential environmental factors likely also contribute by interacting with genetic vulnerabilities. Examples include:
Prenatal Exposures
Exposure to alcohol, tobacco or toxins in utero can increase ADHD risk, potentially by altering gene expression patterns during brain development.
Childhood Adversities
Abuse, neglect or stressful experiences in early childhood are linked to increased ADHD risk. Trauma may modify genetic susceptibilities.
Chemical Exposures
Exposure to environmental toxins like lead or organophosphates from pesticides may potentially interact with genes to influence ADHD behaviors and severity.
Overall, both genetic predispositions and environmental influences likely converge to shape neurodevelopmental pathways and contribute to ADHD onset. However, more research is needed to fully understand these gene-environment interactions.
Conclusion
In summary, while no single “ADHD gene” has been identified, hundreds or more genes appear to contribute small effects that add up to increase inherited risk. The main genes implicated include dopamine and serotonin system genes, synaptic plasticity genes, and neurodevelopmental genes. Additionally, rare mutations and chromosomal copy number variants disrupt genes that offer clues to biological pathways involved. ADHD likely arises from a combination of genetic vulnerabilities interacting with environmental exposures during early neurodevelopment. Ongoing research will further elucidate the precise genetic architecture and biological mechanisms underlying ADHD.