Association of dopamine transporter gene variants with childhood ADHD features in bipolar disorder

Abstract

Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (P = 0.007) and for variants in introns 9 and 13 with mood instability (P = 0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (P = 0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity and mood instability (P = 0.002, 0.007, and 8 × 10(-4), respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits.

Figure 1

The genomic location, structure, and orientation of DAT1 on chromosome 5p15.3 is shown with the relative locations indicated for the 3’ UTR VNTR and the 22 SNPs that we have previously identified (Greenwood et al., 2006). The corresponding haplotype block structure derived from Haploview 4.0 (Barrett et al., 2005) is depicted below with the estimates of pair-wise LD between all SNPs displayed along a gradient from D’=0 (white) to D’=1 (red). Gene start and end points are listed according to Genome Reference Consortium Build 37. The ten SNPs selected for further genotyping in the family and case-control samples are indicated in bold. An asterisk indicates the haplotype tagging SNPs selected based on our previous studies (Greenwood et al., 2002; Greenwood et al., 2006), with the remaing two SNPs selected for their proximity to potential functional variants (Greenwood and Kelsoe, 2003; Guindalini et al., 2006).