Effects of DAT gene polymorphisms and ADHD status on DAT binding measured with PET

Objectives The aim of this study was to examine the relationship between striatal DAT activity in individuals with and without ADHD attending to DAT polymorphisms (SLC6A3) gene (3’UTR and intron 8 variable number of tandem repeats (VNTR) polymorphisms as well as the 3’UTR - intron8 haplotype). We hypothesized that there will be a significant association between these DAT gene polymorphisms (and haplotype) and DAT binding in striatum of ADHD patients.

Methods 70 volunteers between 18 and 55 years of age (ADHD n=34; Controls n=36). Subjects were injected with 5 mCi of 11C Altropane and serial images of the brain were acquired with an HR+ PET camera. Binding potential (BP,k3/ k4) was calculated by the simplified reference region method (cerebellum reference). Genotyping of the 2 DAT (SLC6A3) 3’UTR and intron 8 VNTRs used standard protocols.

Results The gene frequencies of each of the polymorphisms assessed did not differ between the ADHD and control groups. ADHD status (t=3.54; p<001) and 3’UTR of SLC6A3 (8,9 repeat carrier status; t=2.4; p<0.02) were independently and additively associated with increased DAT binding in the caudate. ADHD status accounted for increased striatal (caudate) DAT binding regardless of 3’UTR polymorphism and 3’UTR (8,9 repeat) carrier status accounted for increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron 8 or the 3’UTR-intron8 haplotype with DAT binding.

Conclusions In contrast to the study hypothesis, we did not find an association between the 3’UTR-intron8 haplotype and DAT binding. Instead, we found the 3’UTR polymorphism only to be associated with impaired DAT binding in both ADHD and healthy controls. We also found that both ADHD status and 3’UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3’UTR) of SLC6A3 has functional consequences on CNS DAT binding in humans.

Research Support NIMH grant RO1MH064019 (Dr. Spencer