Haplotype analysis at the DAT1 locus suggests that the variant contributing to ADHD may map to the 3′end of the gene

Mice lacking functional dopamine transporter gene (DAT1) display marked hyperactivity. Cook et al (1995) reported an association between ADHD and the 480bp DAT1 allele. This has been replicated by many groups. Since the variant maps to the 3′ untranslated region of the gene, this allele may not have a direct effect on ADHD. Another variant which may be in linkage disequilibrium with the 480 bp may influence the development of ADHD. Haplotype analysis using the programme TRANSMIT was performed on the DAT1 VNTR, and 5 additional variants including 2 flanking markers; D5S2005 and D5S1981 spanning a region of ∼250 kb. A haplotype of allele 2 (480 bp) of DAT1 VNTR, allele 4 of the DS52005 and 3 of the D5S1981) was significantly transmitted to ADHD cases (Chi-square = 9.1, P = 0.0025). In addition, a highly significant preferential transmission of a haplotype containing allele 2(480 bp) of DAT1 VNTR and allele 3 of the marker D5S1981 (Chi-square = 12.6, P = 0.00044) was observed. A haplotype made of allele 4 of the D5S2005 and the 2 of the VNTR (480 bp) was also preferentially transmitted but was not statistically significant. LD analysis (using EH) showed significant disequilibrium between the VNTR and marker D5S1981 but not between the VNTR and D5S2005. This suggests that the variant at the DAT1 locus contributing to ADHD may map toward the 3′ end of the gene.