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

Authors


  • Conflict of interest: Drs. Greenwood, Joo, Kelsoe, Remick, and Sadovnick and Ms. Shekhtman have no competing financial interests to report. Dr. McElroy is a consultant to or member of the scientific advisory board of Alkermes, Eli Lilly, Teva, and Shire and has received unrelated research support from the Agency for Healthcare Research & Quality (AHRQ), Alkermes, AstraZeneca, Bristol–Myers Squibb, Cephalon, Eli Lilly, Forest Labs, GalaxoSmith Kline, Jazz Pharmaceuticals, Marriott Foundation, Orexigen Therapeutics, Shire, and Takeda Pharmaceutical Company. Dr. McElroy is also an inventor on United States Patent No. 6,323,236 B2 for the use of sulfamate derivatives for treating impulse control disorders and has received payments from Johnson & Johnson Pharmaceutical Research and Development, which has exclusive rights under the patent. Dr. Keck is a co-inventor on a United States Patent (No. 6,387,956) for treating obsessive–compulsive spectrum disorder through tramadol and has received no financial gain.

  • How to Cite this Article: Greenwood TA, Joo E-J, Shektman T, Sadovnick AD, Remick RA, Keck PE, McElroy SL, Kelsoe JR. 2012. Association of Dopamine Transporter Gene Variants With Childhood ADHD Features in Bipolar Disorder. Am J Med Genet Part B 162B:137–145.

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. © 2012 Wiley Periodicals, Inc.

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