Genetic risk and phenotypic variation in attention deficit hyperactivity disorder.
Published: 2004
Language: eng
Number of pages: 188
Subjects: Attention-deficit hyperactivity disorder -- Genetic aspects.; Phenotype.
Description: Genetic factors play a major role in the etiology of Attention Deficit Hyperactivity Disorder (ADHD), as is evident from family, twin and adoption studies. Molecular genetic research has implicated a number of genes as risk factors for ADHD. Despite solid evidence the mode of genetic transmission has been elusive. The difficulty in identifying genes for ADHD may be, at least in part, a reflection of the complex relationship between the causative genes underlying the disorder and their phenotypic expression at the behavioural level. Objective: The immediate goal of this thesis was to investigate specific behavioural traits and potential cognitive endophenotypes in relation to three candidate genes of ADHD; the dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and synaptosomal-associated protein of 25 kDa (SNAP-25). Rather than relying on ADHD as categorical diagnosis of affected or unaffected, inattention and hyperactivity-impulsivity are investigated independently as continuous traits to determine the relationship with the specific genetic risks for ADHD. Different informants were investigated independently by evaluating symptoms reported by parents and by teachers across the two behavioural dimensions. Inhibitory control and working memory were evaluated to determine the relationship with the genetic risks and argued as potential cognitive endophenotypes. Results: The 4-repeat allele of the 48 bp repeat located in the third exon of DRD4 was linked with lower parent-reported symptom scores of inattention. No significant results were found for teacher reported behaviours. Better inhibitory control was linked with the 4-repeat allele. Inattention and hyperactivity-impulsivity as reported by parent, by not teacher, were linked with a risk haplotype of DAT1. No relationship was found between inhibitory control and DAT1. SNAP-25 was linked with higher ratings of both inattention and hyperactivity-impulsivity. No relationship with deficits in verbal working memory was found for any of the genes investigated. In contrast, better working memory was linked with DAT1. Conclusions: The relationship between behavioural and cognitive traits showed variation across the candidate genes investigated, as was broadly predicted. Differentiation of the relationship of traits across genetic risk factors was evident for behavioural dimensions and for informant. The study findings support inhibitory control as a genetically informative endophenotype for ADHD. Overall, these results highlight the potential of quantitative approaches for the elucidation of genetic traits, and underlying genes, in ADHD.
Notes: Adviser:  Russell Schachar.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5453.