Advances in the Genetics of ADHD
The main objectives of the Human Genome Project were to identify disease-related genes, reorganize diagnostic processes, and use the new information to develop improved treatment strategies. The Project has had several successes in the field of medicine,  opening up new doors for future research; however, within the field of psychiatry, little progress has been made.
According to University of Colorado School of Medicine, Department of Psychiatry, Professor Randal Ross, M.D., many of the psychiatric illnesses are rather common and their lifetime prevalence rates sit between one and 40 percent of the population.4 Within the 1990s, the common disease-common variant hypothesis was developed, which stated that common diseases shared a genetic component and that the diseases would be deciphered by the common variants of a limited number of genes, with each variant having a larger effect. For diseases such as diabetes, macular degeneration, and Crohn’s disease, such an approach has proven successful, as common variants of three to 100 genes aid in the explanation of the diseases’ heritability.2 Genetic contributions to the field of psychiatry have not been as successful. According to Ross, psychiatric illnesses may be associated with larger numbers of genes.4 For example, with schizophrenia, genetic contributions may account for 80 percent of the risk factor; however, the risk is explained by common variants of thousands of genes and each variant has a small effect.4 Therefore, even the largest effects of the variants account for only one to two percent of the genetic risk.
An alternative genetic model, the multiple rare variant model, shows which genetic contributions to diseases that are connected to rare variants, with variants having larger effects. However, if there is a common disease and rare variant, a small number of cases will be able to be attributed to a specific variant.4 Therefore, according to Ross, researchers have developed a strategy in which they focus on large deletions or duplications within the genome, a strategy with two advantages. First, the deletions or duplications are large enough to cover an entire gene or even multiple genes. A variation in the number of whole copies is called copy number variants (CNVs).4 It is thought that the alteration in number of whole gene copies will decrease or increase protein production, hopefully to a level that is quite large.4 Second, as beginning and end points of gene deletion and duplications varies among individuals, the deletions are large enough to overlap, and persons with overlapping deletions and duplications can be grouped together.4
To examine large, rare variant contributions to ADHD, Williams and colleagues used the CNV approach. Their sample included 2,400 individuals, with 700 children and adolescents—all of European ancestry.8 Williams and colleagues found that the group with ADHD had 1.15 times more large CNVs than those without ADHD.8 The increased CNVs were associated with genes that have already been identified as potential risk factors for schizophrenia and autism.8 While there were no real significant differences in duplications, they were slightly higher in the ADHD group, mainly at chromosome 15q13.3, the location of CHRNA7.8
Stergiakouli and colleagues went beyond Williams and colleagues by integrating the common disease-common variant and the multiple rare variant hypotheses. Using the subsample of the cases used by Williams and colleagues, as well as a larger Icelandic sample, Stergiakouli and colleagues found that there were several loci where common variants may be associated with ADHD—an already known fact.9 However, they also found that the same gene identified by Williams and colleagues, CHRNA7, was the site of most duplications.9 Both groups note that for families that carry the CHRNA7 duplication associated with ADHD, it remains unclear how often ADHD occurs in children who inherit such duplications.9
Overall, identifying genetic contributors to psychiatric illnesses has not been an easy task. Researchers hope that in the future more information will be obtained to provide new medication targets and identify biomarkers that identify subtypes of illnesses.
 US Department of Energy and US Department of Health and Human Services: Understanding Our Genetic Inheritance: The US Human Genome Project: The First Five Years: FY 1991–1995 (DOE/ER-0452P, NIH publication no 90–1590). Washington, DC, US Department of Commerce, National Technical Information Service, 1990.
 Lander ES: Initial impact of the sequencing of the human genome. Nature 2011; 470:187–197.
 Green ED; Guyer MSNational Human Genome Research Institute: Charting a course for genomic medicine from base pairs to bedside. Nature 2011; 470:204–213.
 Ross, R.G. (2012). Advances in the Genetics of ADHD. Am J Psychiatry 169(2): 115-117.
 Lander ES: The new genomics: global views of biology. Science 1996; 274:536–539.
 Purcell SM; Wray NR; Stone JL; Visscher PM; O’Donovan MC; Sullivan PF; Sklar P; International Schizophrenia Consortium: Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460:748–752.
 Singleton A; Hardy J: A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Hum Mol Genet 2011; 20(R2):R158–R162.
 Williams NM; Franke B; Mick E; Anney RJL; et al: Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry 2012; 169:195–204.
 Stergiakouli E; Hamshere M; Holmans P; Langley K; et al; deCODE Genetics: Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD. Am J Psychiatry 2012; 169:186–194.