Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):137-45. doi: 10.1002/ajmg.b.32108. Epub 2012 Dec 19.
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.
双相情感障碍 (BD) 和注意缺陷多动障碍 (ADHD) 表现出极高的共病率，以及家族共分离模式。流行病学数据表明，这些疾病要么共享共同的遗传结构，要么 BD 中的 ADHD 特征可能代表一种具有不同病因的亚型。我们之前使用 Wender Utah 评定量表 (WURS) 评估了 BD 家族中的 ADHD 特征，并确定了与冲动、情绪不稳定和注意力不集中相关的三个可遗传因素。连锁分析显示，注意力不集中因子在 5p15.3 上与多巴胺转运体基因 (DAT1) 附近的遗传分数为 1.33，DAT1 与 BD 和 ADHD 均有关联。药物学证据也表明 DAT 在这两种疾病中都有作用。我们现在在一个重叠的 87 个 BD 家族样本中评估了 10 个 DAT1 变体与 WURS 总分和因子的关联。在 WURS 测量中观察到三个 SNP 的显著关联，特别是在 WURS 总分的内含子 8 中的 SNP（P = 0.007）和内含子 9 和 13 中的变体与情绪不稳定（P = 0.009 和 0.004）。对 52 个 BD 病例和 46 个健康对照者的独立样本的分析进一步支持了内含子 8 变体与情绪不稳定的关联（P = 0.005），并通过联合分析证实了该 SNP 与 WURS 总分的关联。冲动和情绪不稳定（P = 0.002、0.007 和 8 × 10(-4)）。这些数据表明，DAT1 内的变体可能使一个以早期前驱特征为特征的 BD 亚型易感，这些特征包括注意力缺陷。
