Genomics: Insight

Section 1: Overview of ADHD

ADHD affects around 6 million children between the ages of 3 and 17.¹ Of the children diagnosed with ADHD, about 60% of them have symptoms that persist into adulthood. Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that can present itself through an ongoing pattern of inattention, hyperactivity, and/or impulsivity, and it is typically associated with a variety of negative outcomes, including high dropout rates from school, social barriers, criminal behaviors, and professional failures. Each outcome has very serious impacts on individuals, families, and society as a whole. Currently, common treatments for ADHD include behavioral therapy, parental training, and medication. However, there is a limitation in terms of the current treatments for early diagnosis and effective treatments.

Section 2: What genes are involved?

It is important to understand the molecular basis of ADHD. Genome-wide association studies (GWAS) examine the likelihood of specific genetic sequences being predictive of traits such as ADHD. Interest in the dopaminergic system in ADHD has come from pharmacological, animal, and imaging studies.¹ Dopamine is a neurotransmitter chemical made in the brain that is associated with attention.² Low levels of dopamine activity are associated with less regulation of attention, a symptom of ADHD. Stimulant medication reduces ADHD symptoms and inhibits the reuptake of dopamine, thus increasing extracellular concentration. Imaging studies of patients with ADHD provide evidence of changes in brain regions where dopaminergic systems are more active.³ Animal studies, such as work on the DAT (dopamine transporter) knockout mouse which manifests ADHD-like behavior, have also implicated dopaminergic systems.⁴ All this evidence has led to the further investigation of the dopamine D4 receptor gene (DRD4), dopamine D5 receptor gene (DRD5), dopamine transporter gene (SLC6A3 or DAT1), and catechol-o-methyltransferase (COMT).

All this evidence has led to the further investigation of DRD4, DRD5, SLC6A3 or DAT1, and COMT.

DRD4 is the D4 receptor that binds with both dopamine and noradrenaline, and a mutation in this gene has been reported to influence cognitive performance.⁵ DRD5 is another dopamine receptor gene in which mutations of a single nucleotide show an association with ADHD. Dopamine transporter gene SLC6A3 was initially considered the most likely candidate gene for ADHD because it is responsible for the reuptake of dopamine and is the target of stimulant medication. COMT is an enzyme catalyzing the degradation of dopamine, adrenaline, and noradrenaline. Quantitative association studies have shown correlations between ADHD symptoms and mutations in COMT.⁶

A study by A. Thapar et al. from 2010⁷ shows the association between the DRD4-7 and DRD4-5 alleles (variant forms of a gene) and ADHD. They showed the association of those alleles by comparing allele frequencies through 3 different family-based studies (the parents of kids with ADHD serve as the controls) and case-control studies (ADHD patients are compared to healthy controls). Their results revealed the tightest association between the DRD4-7 repeat allele and ADHD. A variety of other genes were also examined, but the association between those genes and ADHD was not high enough to be statistically significant.

In another study that examines DRD4 association with ADHD, H. Zhang et al. demonstrate that a single nucleotide polymorphism in the DRD4 gene– the gene we previously identified as having the strongest correlation with ADHD– is associated with changes in neurological activity and functional connectivity in children with ADHD. Homozygosity for the T allele (TT, both copies of the allele are T) in DRD4 is more closely associated with severe ADHD symptoms than those with the CT allele (refers to heterozygous, or different forms of an allele). The data shows that the TT allele is part of the gene that causes behavioral discrepancies, such as learning problems, psychosomatic disorders, anxiety, and attention accuracy.

Section 3: How Gene-Environment correlation influences ADHD symptom severity

In addition to an association between a gene and ADHD symptoms, environmental factors play a huge role in influencing the effect of genetics on ADHD symptom severity. E. Sciberras8 et al. found some key environmental factors that influence ADHD are maternal psychopathy and family conflicts, also known as environmental adversity, classified as adversity towards different environmental factors. M Rutter et al. also found adverse childhood experiences and environmental risk factors can lead to ADHD.⁹

… key environmental factors that influence ADHD are maternal psychopathy and family conflict…

M. Martel et al. showed that the association between the DRD4 allele and ADHD is influenced by the parenting environment.¹⁰ The study shows that the high-risk ADHD genotype relative to the low-risk ADHD genotype results in significantly higher symptom severity only in the presence of an environmental risk factor, such as inconsistent parenting. Interestingly, there is no difference in ADHD symptom severity in the presence of consistent parenting.

It was also shown in the same study that children’s high self-blame in marital conflicts is an environmental risk factor that significantly increases the severity of inattention symptoms associated with ADHD.¹¹ Interestingly, in the absence of the aggravating environmental influence (i.e., no or low self-blame), there is no significant difference in inattention severity between low and high risk.

Section 4: Conclusion + perspectives

It is clear based on the data described that there is a significant association between DRD4 and parental risk factors. With ADHD diagnoses significantly rising over the past decade, it is important to continue to understand the interaction between environmental factors and the genetics behind ADHD, and how we cannot look at the two factors separately. Both factors need to be explored together. We wanted to write about ADHD to further understand and support those with ADHD. While exploring this topic, we gained a new perspective by realizing just how intertwined environmental factors and ADHD are.

… there is a significant association between DRD4 and parental risk factors…

References

1. “Dopamine genes and attention-deficit hyperactivity disorder: a review” https://pubmed.ncbi.nlm.nih.gov/12587848/
2. “In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter” https://pubmed.ncbi.nlm.nih.gov/15950001/
3. “Dopamine transporter mutant mice in experimental neuropharmacology” https://pubmed.ncbi.nlm.nih.gov/18057916/
4. “Advances in genetic findings on attention deficit hyperactivity disorder” https://pubmed.ncbi.nlm.nih.gov/17506925/
5. “An Overview on the Genetics of ADHD” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854824/
6. “Effects of the DRD4 −521 C/T SNP on Local Neural Activity and Functional Connectivity in Children With ADHD” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772420/
7. “Prenatal Risk Factors and the Etiology of ADHD-Review of Existing Evidence” https://pubmed.ncbi.nlm.nih.gov/28091799/
8. “The Dopamine Receptor D4 Gene (DRD4) Moderates Family Environmental Effects on ADHD” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306231/
9. “The Dopamine Receptor D4 Gene (DRD4) Moderates Family Environmental Effects on ADHD” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306231/ Replace