A great deal of research has been carried out on the genetic factors that may play a role in attention deficit hyperactivity disorder (ADHD). Over 1,800 studies have been published on the subject to date.
These studies, including family studies as well as those centered on specific genes or genome-wide screening, have produced strong evidence that genes play a role in susceptibility to ADHD. A 2009 review concluded that genetics account for 70 to 80 percent of the risk, with a mean estimate of 76 percent.
Specific gene studies have produced good evidence linking certain genes to the disorder, particularly the dopamine D4 (DRD4) and dopamine D5 (DRD5) genes. However, it is difficult to implicate any specific gene in ADHD “beyond reasonable doubt,” due to the diversity and complexity of the condition.
Dr. Tobias Banaschewski of the Central Institute of Mental Health in Mannheim, Germany, explains that, “Twin and adoption studies show ADHD to be highly heritable.” He writes, “In recent years, a large number of studies on different candidate genes for ADHD have been published. Most have focused on genes involved in the dopaminergic neurotransmission system.”
ADHD is linked to deficits in the functioning of several brain areas, including the prefrontal cortex, the basal ganglia, cerebellum, temporal and parietal cortex. These areas are important in brain activities that may be impaired in ADHD, such as response inhibition, memory, planning and organization, motivation, processing speed, inattention and impulsivity.
Gene studies, whether focusing on specific genes or scanning the whole genome, aim to link DNA variations with these observable symptoms. They also endeavor to locate the relevant chromosome regions.
A recent 2010 analysis of genome-wide studies found only one confirmed location on one chromosome (chromosome 16) that has been repeatedly linked to ADHD. The authors say, “This is not unexpected because the power of individual scans is likely to be low for a complex trait such as ADHD which may only have genes of small to moderate effects.”
While current results from ADHD genome-wide studies are far from conclusive, they do provide new directions and suggest research avenues to follow, the analysts say. Dr. Banaschewski comments, “To date, the findings from genetic studies in ADHD have been somewhat inconsistent and disappointing. Specific gene-based studies have similarly only explained a small percentage of the genetic component of ADHD. Despite the high heritability of the disorder, genome-wide studies have not shown extensive overlaps, with only one significant finding in the meta-analysis of studies [chromosome 16].” But he adds that “the latter approach is likely to redirect future ADHD research, given the apparent involvement of new gene systems and processes.”
“In conclusion,” Dr. Banaschewski writes, “genetic studies have started to unravel the molecular architecture of ADHD, and several new exciting directions have recently been suggested.”
He thinks that, even if the ADHD risk genes have small effect sizes in the population, their identification may still be highly relevant clinically, because gene variants may explain most of the heritability in individual patients. What’s more, our understanding of their functions, and the pathways between each gene and behavior, may translate into improved diagnosis and treatment strategies.
For example, Dr. Mark Stein of the University of Illinois at Chicago suggests that the individual differences in response to ADHD drugs could be genetic, so the more we know about the genes involved, the more individualized treatment can become. In fact, drug trials are already showing relationships between treatment response and particular gene markers in ADHD. This could improve not only patient outcomes but also increase long-term compliance to treatment regimens.
As with other types of risk factor associated with ADHD, an individual’s genetic make-up is neither sufficient nor necessary to cause it, but may increase their overall risk. Gene-environment interactions, which are as yet unclear, are also likely to be of importance when understanding the role of genes in ADHD.
Dopaminergic neurotransmission system: DRD4, DRD5, DAT1/SLC6A3, DBH, DDC.
Noradrenergic system: NET1/SLC6A2, ADRA2A, ADRA2C).
Serotonergic system: 5-HTT/SLC6A4, HTR1B, HTR2A, TPH2.
Neurotransmission and neuronal plasticity: SNAP25, CHRNA4, NMDA, BDNF, NGF, NTF3, NTF4/5, GDNF.
Psychiatric GWAS Consortium Coordinating Committee. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. The American Journal of Psychiatry, Vol. 166, May 2009, pp. 540-56.
Zhou, K. et al. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. American Journal of Medical Genetics; Neuropsychiatric Genetics, Vol. 147B, December 5, 2008, pp. 1392-98.
Banaschewski, T. et al. Molecular genetics of attention-deficit/hyperactivity disorder: an overview. European Child and Adolescent Psychiatry, Vol. 19, March 2010, pp. 237-57.
Kebir, O. et al. Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies. Journal of Psychiatry and Neuroscience, Vol. 34, March 2009, pp. 88-101.
National Institute for Health and Clinical Excellence (NICE). Attention deficit hyperactivity disorder: Full guideline, September 2008. (PDF file)
Stein, M. A. and McGough, J. J. The pharmacogenomic era: promise for personalizing attention deficit hyperactivity disorder therapy. Child and Adolescent Psychiatric Clinics of North America, Vol. 17, April 2008, pp. 475-90.