Genomics: Insight

Research Question: What risk genes can be linked to ADHD?

Introduction 

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disease that includes symptoms such as difficulty in concentration, impulsivity, hyperactivity, and inattention. Around 3-5% of children struggle with ADHD worldwide,(Olfson 2024), which in turn can affect how they contribute to society as adults. Researchers have discovered that ADHD is highly heritable, indicating that genetics is a significant factor in its development. In fact, studies indicate that inherited genes from parents may be responsible for between 70-80% of ADHD instances (Olfson 2024). 
According to recent studies in 2024, ADHD may also be caused by rare genetic changes called de novo mutations (Olfson 2024). De novo mutations are genetic alterations that do not come from parents but rather develop spontaneously in a child's DNA. Some of these mutations can alter the way specific genes function and are referred to as ultra-rare de novo harmful mutations since they only happen in a small percentage of people. The reason these mutations are deemed "damaging" is that they have the potential to interfere with vital biological functions, such as brain development.

"DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants..."
 

Discovering risk genes 

According to a U.S. study conducted in 2024 (Olfson 2024), the analysis of biological parents and child genomes has identified many ADHD risk genes, such as missense, frameshift, and truncated (premature stop codon) variations. Through clinical interviews and whole-exome DNA sequencing, 147 parents-ADHD child trios were used (152 families in total), where geneticists found 24 ultra-rare damaging mutations in 23 individuals. Parent child trios refer to the comparing of a child’s genomes to their biological parents. At least one parent had ADHD, and was compared with the trios of parent-child with no ADHD (control sample). The results concluded that there was no overlap of de novo damaging mutations between ADHD trios and control trios. Another study, which calculated the genetic risk/predisposition of an individual using genetic information (PCR analysis), found similar variants overlapping between ADHD children and adults (Rovira 2020). The genes involved with these mutations included YLPMI, CTNND2, GNB2L1, and a high-confidence risk gene called lysine demethylase 5B (KDM5B). The term high-confidence risk genes refers to when mutations and or variations within a gene are shown to lead to an increased likelihood of the development of a disorder or disease.  YLPMI aids in RNA processing by maintaining telomeres and RNA polymerase, CTNND2 encodes an essential nervous system protein called delta-catenin that allows for cell function, and GNB2L1 regulates cell movement and processes. Although these genes are associated with ADHD when mutated, a definitive prognosis of predisposition is not clear as there is currently not enough research regarding all of the factors that causes ADHD from childhood to adulthood. Many other developmental disorders overlap with similar gene mutations such as intellectual disability/ developmental delay in children with autism (Olson 2024), making predictions difficult. 
Finally, KDM5B is a histone-modifying enzyme that plays a role in epigenetic regulation of gene expression. Through demethylation, KDM5B removes a methyl group from lysine 4, which is located on histone 3 (H3K4 demethylase). Rare and damaging variants in KDM5B result in a spectrum of different phenotypic changes, ADHD is thought to be included in this spectrum (Olfson 2024).        
Based on a review of KDM5B and its effect in developmental disorders (DDs), KDM5B has been associated with autosomal recessive inheritance, meaning that the mutations involve autosomal chromosomes and is not dominant in gene expression. (Harrington 2022). By working on reducing symptoms from these genetic mutations through pharmaceutical medicine and gene therapy (the usage of viruses in targeted gene transference) (Wang 2019), ADHD symptoms can decrease and possibly lead to an improvement in concentration and function. 
 

Conclusion

In conclusion, there has been a strong genetic correlation in adults and children with ADHD (Rovira 2020). Through genetic testing and the more recent de novo damaging variant detection, risk genes such as KDM5B have opened new doors to possibly new pharmaceutical approaches and treatments. 
Even though ADHD can be passed down through genes, the environment also plays a part. Things like if a mom smokes or drinks during pregnancy, or if a baby is born too small, can raise the risk of getting ADHD. Stressful experiences when someone is little can also make a difference. Thapar and others (2013) say these things can mix with a person’s genes and affect how strong their ADHD symptoms are.
Overall, with the growing prevalence of ADHD in children, it is important to understand possible risk factors that could contribute to predisposition. With growing science and technology, these new genes are being discovered and, hopefully, aid in possible prevention for future generations.
 

References

1. Harrington, Jack, et al. “Pathogenic KDM5B Variants in the Context of Developmental Disorders.” Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1865, no. 5, July 2022, p. 194848, https://doi.org/10.1016/j.bbagrm.2022.194848. Accessed 5 Oct. 2022.
2. Olfson, Emily, et al. “Rare de Novo Damaging DNA Variants Are Enriched in Attention-Deficit/Hyperactivity Disorder and Implicate Risk Genes.” Nature Communications, vol. 15, no. 1, 12 July 2024, https://doi.org/10.1038/s41467-024-50247-7.
3. Thapar, A., Cooper, M., Eyre, O., & Langley, K. (2013). What have we learnt about the causes of ADHD? Journal of Child Psychology and Psychiatry, 54(1), 3–16. https://doi.org/10.1111/j.1469-7610.2012.02611.x
4. Rovira, P., Demontis, D., Sánchez-Mora, C. et al. Shared genetic background between children and adults with attention deficit/hyperactivity disorder. Neuropsychopharmacol. 45, 1617–1626 (2020). https://doi.org/10.1038/s41386-020-0664-5
5. Wang, D., Tai, P.W.L. & Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 18, 358–378 (2019). https://doi.org/10.1038/s41573-019-0012-9