Association analysis of norepinephrine transporter polymorphisms and methylphenidate response in ADHD patients

Methylphenidate (MPH) is the most frequently prescribed drug in Attention Deficit Hyperactivity Disorder (ADHD). Hitherto mostly the dopamine transporter gene has been studied in MPH-response and only a few studies analyzed the norepinephrine transporter (NET, SLC6A2) gene, although MPH is a potent inhibitor of both dopamine and norepinephrine transporters. We aimed to analyze this monoamine transporter gene in relation to ADHD per se and MPH-response in particular to gain further knowledge in ADHD pharmacogenetics using a Caucasian sample.

Six single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143, rs3785157, rs5569, rs7194256 SNP) were studied across the NET gene in 163 ADHD children (age: 9.3±2.6; 86.5% male) using ADHD-RS hyperactivity-impulsivity and inattention scales. For case-control analysis 486 control subjects were also genotyped. At the MPH-response analysis responders had minimum 25% decrease of ADHD-RS total score after 2months of treatment, and chi-square test compared 90 responders and 32 non-responders, whereas ANOVA was used to assess symptom improvement after the first month among the 122 ADHD patients.

The classical case-control analysis did not yield any association with ADHD diagnosis, which was supported by meta-analysis conducted on the available genetic data (combining previously published and the present studies). On the other hand, the intronic rs3785143 showed nominal association with inattention symptoms (p=0.01). The haplotype analysis supported this association, and indicated the importance of the first haploblock encompassing the intronic and 2 promoter SNPs. With MPH-response only the promoter rs28386840 showed nominal association: Those with at least one T-allele were overrepresented in the responder group (42% vs 19%, p=0.08), and they had better improvement on the hyperactivity-impulsivity scale compared to the AA genotype (p=0.04).

Although none of our single SNP findings remained significant after correcting for multiple testing, our results from the MPH-response analysis indicate the potential importance of promoter variants in the NET gene.