December 2003

From Molecular Psychiatry

The dopamine receptor D1 gene and ADHD: A piece of the genetic puzzle?

Attention-deficit/hyperactivity disorder (ADHD) is recognized as the most prevalent mental health disorder of childhood, affecting about 3 to 5 percent of school-age children worldwide. The hallmarks of the disorder are age-inappropriate levels of inattention, hyperactivity and impulsiveness. These problems often lead to underachievement in school and can have a negative impact on interpersonal relationships and on self-esteem. ADHD symptoms often persist into adolescence and adulthood, resulting in lifelong difficulties in academic, occupational, social and family functioning. In addition, there is evidence that ADHD may be a risk factor for other serious mental health problems and specific learning disabilities. All told, ADHD is a major public health issue.

Twin, family and adoption studies have produced strong evidence that ADHD is, in large part, genetically determined. Inheritance of the disorder is complex. Multiple genes, each of small to moderate effect, are likely to be involved. Although the neurobiological basis of ADHD remains to be fully understood, there is much evidence pointing to dysregulation of the dopamine neurotransmitter system as an underlying factor. Because of this, genes of the dopamine system are considered as candidates for involvement in the disorder. Genes that have been investigated are the ones encoding the five receptors in the brain, D1D5, through which dopamine acts. Such studies, to date, have found strong evidence for the involvement of two of these receptor genes, those encoding the D4 and D5 receptors, but little or no evidence for the involvement of either D2 or D3. Recently, the authors obtained evidence for involvement of the remaining member of this class of genes, the gene encoding dopamine receptor D1 (DRD1).

Combined evidence from a number of human and animal studies suggested DRD1 to be a particularly strong candidate for involvement in susceptibility to ADHD. To test this, the authors investigated the inheritance patterns of four DNA changes (situated at various positions across the DRD1 gene) in a large sample of small families, each having at least one child diagnosed with the disorder. These children were more likely to have inherited one particular combination of the DNA changes, as compared to other combinations. Furthermore, when this genetic combination was analyzed in relation to the behavioral symptoms exhibited by the children, the authors found a relationship with the inattentive symptoms of ADHD, but not the hyperactive/impulsive symptoms. Together, these findings support the proposed involvement of DRD1 in ADHD, and in particular, in genetic risk for the inattentive symptoms of the disorder. These findings represent the first reported evidence for involvement of the DRD1 gene in ADHD. It is important to note, however, that these findings will await future replication in additional, independent samples of ADHD families before definitive conclusions can be made. Also, since the four DNA changes analyzed in this study are not predicted to change the function of the DRD1 gene, studies aimed at identifying a functional DNA change will also be important. In this regard, the "risk combination" the authors identified could serve as a landmark indicating the presence of a functional change nearby, and thereby guide the search for DNA changes in the DRD1 gene contributing to ADHD.

Citation source: Molecular Psychiatry advance online publication, December 2003 (doi:10.1038/sj.mp.4001440)

For further information on this work, please contact Dr. Virginia L Misener, PhD., Toronto Western Research Institute-University Health Network, Toronto Western Hospital, 399 Bathurst St., Toronto, Ontario M5T 2S8, Canada. Phone: 416-603-5800 x2940, FAX: 416-603-5126, E-mail: gmisener@uhnres.utoronto.ca

Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: +1-310-825-7113; FAX: +1-310-206-6715; e-mail: licinio@ucla.edu

For a copy of this article, please contact Aimee Midei, Editorial Assistant, e-mail: molecularpsychiatry@mednet.ucla.edu.

PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.

ARTICLE: "Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder"

AUTHORS: Virginia L Misener, Paola Luca, Obehi Azeke, Jennifer Crosbie, Irwin Waldman, Rosemary Tannock, Wendy Roberts, Molly Malone, Russell Schachar, Abel Ickowicz, James L Kennedy, Cathy L Barr

Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychology, Emory University, Atlanta, Georgia, USA; Brain and Behaviour Program, The Hospital for Sick Children, Toronto, Ontario, Canada Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada; Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada











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