| Attention deficit hyperactivity disorder (ADHD) is one of the most heritable complex disorders. Even with its high heritability, genome-wide scans do not show consistent results and candidate gene approaches have not been replicated in many cases. Such inconsistent results indicate the lack of a major gene effect, which reinforces the multigenic nature of ADHD, suggesting contributions from a large number of genes. In order to detect genetic contributions for mapping complex diseases, linkage disequilibrium (LD) has been the focus of recent research. Haplotype association studies use haplotypes that consist of several polymorphisms usually in linkage disequlibrium near the gene region, and consistently show better detection than single marker studies.; Through this thesis research, several important considerations in haplotype association studies were recognized. Two LD measurements, D' and r2, differ depending on the relationship between polymorphisms, so it is critical to consider which combination of polymorphisms best captures the existence of risk alleles. Another consideration is that there may be several or more polymorphisms in a haplotype block that affect a phenotype in either a causative or a protective way. The third distinct point is that the detection power varies depending on the choice of association testing and the contribution of a polymorphism to the disorder.; Three candidate genes, the dopamine transporter gene (SLC6A3 ), the dopamine D4 receptor gene (DRD4), and the alpha2-noradrenergic receptor gene (ADRA2A), were selected depending on the catecholamine pathway, which is suspected to play a role in modulating the major psychopathology of ADHD. Recognizing the importance of phenotypes in association studies, gender difference and refined phenotypes were also studied. For gender difference, the data suggest that genetic susceptibility to ADHD is regulated differently in girls and boys. This posits important differences in the genetic susceptibility of the nervous system between genders, suggesting that the same polymorphism performs differently due to gender differences in dosage sensitivity in the catecholamine system.; This study reveals the association between all three candidate genes and ADHD supporting the catecholamine pathway as a main etiology. Through this research, possible major reasons for difficulties in mapping complex traits are identified. Moreover, by adding more clarification to the gender difference and phenotype of ADHD, this study provides a basic starting point for understanding the genetic etiology of ADHD. |
