Five novel genetic variants associated with attention-deficit/hyperactivity disorder (ADHD) have been identified by exploiting genetic overlap between ADHD and educational attainment. The discovery was published in the February 2018 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.1
An accompanying editorial in the journal said the discovery is "an important milestone for ADHD genetics” as this is the first paper to identify some of the first common genetic variants associated with ADHD using genome-wide association studies (GWAS). 2
The researchers used advanced statistical tools to analyze large genetic datasets from GWAS on ADHD in 3000 patients and educational attainment (EA) in more than 300,000 individuals.
Alexey A. Shadrin, PhD, lead author of the study and postdoctoral research fellow at the Norwegian Centre for Mental Disorders Research (NORMENT), said in a statement that the study sought to “explore the genetic architectures of ADHD and educational attainment and to what degree they have a shared genetic basis." He said the findings “may increase the understanding of the genetic risk underlying ADHD and its connection to educational attainment, which has important socioeconomic and health-related life implications.
"However, the researchers cautioned that they don’t know in what way these genetic variants exert their influence on ADHD risk and EA, and that further studies are needed.
The prevalence of ADHD is estimated to be 5% in school-aged children and 2.5% in adults, and the heritability of ADHD is one of the highest reported among psychiatric disorders, the study pointed out.
ADHD is associated with lower levels of EA. The study said the percentage of US adolescents not completing high school is 5%, but for adolescents with ADHD, the figure jumps to 35%. ADHD is linked to comorbidities that are also associated with lower EA, such as learning disabilities, mood disorders, and disruptive behavior, which are associated with lower EA. Clinical and cognitive symptoms of ADHD may also impact EA.
The data originated from the Psychiatric Genomics Consortium and the Social Science Genetic Association Consortium, respectively."Interestingly, we found evidence for a shared genetic basis between ADHD and educational attainment, in which the majority of ADHD genetic risk variants were associated with lower educational attainment," said professor Ole A. Andreassen, MD, PhD, senior author of the study and director of NORMENT. "This finding suggests that part of the reason for why individuals with ADHD tend to have academic underachievement may be driven by genetic risk.”
The authors report 5 novel genetic loci (locations on the chromosome) associated with ADHD, of which 3 were also shared with educational attainment. Four of the 5 ADHD-associated loci implicate protein coding genes: KDM4A, MEF2C, PINK1, RUNX1T1. The researchers also found a pronounced negative genetic correlation (as 1 factor increases, the other decreases) between ADHD and EA supporting a shared genetic basis between these phenotypes.
While the study does not have any takeaways relevant for clinical practice or treatment, the authors wrote that “evidence for a shared genetic basis between ADHD and educational attainment adds to the conceptual framework for why children with ADHD tend to have academic underachievement and emphasizes the need for ongoing therapeutic interventions for children with ADHD in the school setting.”"
It is important to treat identified genetic associations with caution, bearing in mind that their effect sizes are tiny. This makes them uninformative for clinical diagnostics or treatment guidance, yet they may provide important clues into disease biology that may be interrogated in experimental studies,” says Olav B. Smeland, MD, PhD, who is currently working as a psychiatric resident and postdoctoral research fellow at Oslo University Hospital. "Although we have some idea how the genes work, we could learn more about them by blocking the function of each gene in mice and study the impact on brain function."
Lauren M. Mc Grath, PhD, author of the editorial, wrote that “the strategy for identifying these genetic variants, by leveraging a large-scale genetic study of educational attainment, is also relevant for many early-onset phenotypes, especially learning disabilities and externalizing disorders. The findings also raise important questions about the mechanisms underlying overlapping genetic risk for ADHD and educational attainment. Given the surprising degree of cross-disorder genetic sharing that is being uncovered across psychiatric disorders, understanding the mechanisms underlying shared genetic risk is one of the most important upcoming challenges for psychiatric genetics.”
1. Shadrin AA, Smeland OB, Zayats T. et al. Novel loci associated with attention-deficit/hyperactivity disorder are revealed by leveraging polygenic overlap with educational attainment. J Am Acad Child Adolesc Psychiatry. 2018;57(2):86-95. doi: 10.1016/j.jaac.2017.11.013.
2. McGrath, LM. Two GWASS are better than one: Enhancing genetic discovery for developmental phenotypes. J Am Acad Child Adolesc Psychiatry. 2018;57(2):77-79. doi: 10.1016/j.jaac.2017.11.018.