No Evidence of an Association between Norepinephrine Transporter Gene Polymorphisms and Attention Deficit Hyperactivity Disorder

Abstract

Neurobiological and pharmacological research has suggested that dysregulation of the central noradrenergic systems might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Previous studies have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 G1287A and –3081(A/T) polymorphisms with ADHD in Korean children and adolescents, and to determine the relationships of the genotypes of these two polymorphisms with continuous performance test results and the Junior Temperament and Character Inventory profiles of ADHD. In a case-control study, we assessed 186 ADHD probands and 150 normal controls; 109 trios were studied in a family-based association analysis. There were no significant differences in the genotype or allele frequencies of the SLC6A2 G1287A and –3081(A/T) polymorphisms between the ADHD and control groups (p > 0.05). In the transmission disequilibrium test analyses, there was no evidence for biased transmission of any of the alleles of the SLC6A2 G1287A and –3081(A/T) polymorphisms. In the haplotype analyses of these two polymorphisms, the global and individual χ² tests showed no significant associations between any of the haplotypes and ADHD. There were no significant differences with respect to the continuous performance test results and the Junior Temperament and Character Inventory profiles in the ADHD probands according to the genotypes of the SLC6A2 G1287A and –3081(A/T) polymorphisms. Our findings do not support SLC6A2 as a major genetic susceptibility factor in ADHD.

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample

“…This SNP was shown to downregulate the expression of SLC6A2 significantly, representing a very interesting candidate for molecular genetic studies in ADHD. In contrast to the results reported by Kim et al (2006) and Joung et al (2010) and in line with the findings of Cho et al (2008), we did not detect significant transmission disequilibrium for the T-allele in our sample (Kim et al 2006;Joung et al 2010;Cho et al 2008). Our study is based on family data and provides robust results against stratification admixture in contrast to case-control studies.…”

“…Though Kim et al (2008) further underlined the importance of SLC6A2 in ADHD by an extended association study, the T-3081A variant was not included in the set of investigated variants. In a recent combined case-control and family-based study on Korean children affected by ADHD, Cho et al (2008) were not able to confirm the association for the T-3081A SNP, while Joung et al reported association in a further Korean sample with relatively high odds ratios (Cho et al 2008;Joung et al 2010).…”

Candidate gene studies of ADHD: a meta-analytic review

“…Data were available for meta-analysis from three TDT Brookes et al 2006a;Kim et al 2008) and two Case-Control/HHRR (Cho et al 2008a;Guan et al 2008) studies. Given that no previous studies had reported a signiWcant association between this polymorphism and ADHD, no 'risk' allele was indicated.…”

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

“…Studies have been conducted with a limited number of single-nucleotide polymorphisms (SNPs) within SLC6A2, [21][22][23][24][25] including a functional SNP in the promoter region, [26][27][28] and arrays of tag SNPs covering the entire gene. [29][30][31][32][33] To summarize previous findings and a recent meta-analysis, 34 5 SNPs within SLC6A2 (rs3785157, rs998424, rs3785143, rs11568324, rs28386840) were shown to be associated with ADHD (details provided in Appendix 1, Table S1 and Fig.…”