Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios

The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5-HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5-HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity-impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5-HTTLPR and ADHD (chi2 = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case-control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population.