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Increased Dopamine Transporter Availability Associated with the 9-Repeat Allele of the SLC6A3 Gene

¹ Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
² Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut
³ VA Connecticut Healthcare System, West Haven, Connecticut
⁴ Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut

A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). This polymorphism has 2 common alleles, designated as 10-repeat (_*10R) and 9-repeat (_*9R), that have been linked with several human clinical phenotypes. Previous investigations of the effects of the SLC6A3 polymorphism on DAT availability in smaller samples of humans have yielded divergent results. Methods: We assessed genotype at the SLC6A3 promoter VNTR polymorphism in 96 healthy European Americans (age range, 18–88 y) who also underwent SPECT with ¹²³I-2ß-carbomethoxy-3ß-(4-iodophenyl)tropane (ß-CIT) for measurement of striatal DAT protein availability. A ratio of specific to nondisplaceable brain uptake (i.e., V₃'' = [striatal -occipital]/occipital), a measure proportional to the binding potential, was derived. For this analysis, 9–9 homozygotes and 9–10 heterozygotes were grouped as SLC6A3_*9R carriers and contrasted with SLC6A3_*10R homozygotes. Results: The SLC6A3_*9R carriers had significantly higher striatal DAT availability (V₃'') than did the SLC6A3_*10R homozygotes, controlling for age (F_1,93 = 6.25, P = 0.014, analysis of covariance). The _*9R carriers (n = 41, 49.8 ± 19.5 y) had a mean increase in striatal DAT availability of 8.9% relative to the _*10R homozygotes (n = 53, 49.9 ± 19.2 y). Striatal subregion analysis revealed that the effect of DAT genotype was significant for both the caudate and the putamen. Conclusion: These results support the interpretation of higher DAT levels in association with the _*9R allele in European Americans and may relate to previously observed associations between DAT genotype and neuropsychiatric diseases.

Key Words: ¹²³I-ß-CIT • SPECT • dopamine transporter • genotype • VNTR

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