Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature. Participants (n = 143) were aged 12–30 years and comprised 62 first-degree relatives of bipolar patients (deemed ‘at-risk’), 55 controls, and 26 patients with established bipolar disorder; all were unrelated Caucasian individuals with complete data across the three required modalities (structural magnetic resonance imaging, neuropsychological and genetic data). A DRD2 haplotype was derived from three functional polymorphisms (rs1800497, rs1076560, rs2283265) associated with alternative splicing (i.e., D2-short/-long isoforms). Moderated mediation analyses explored group differences in relationships between this DRD2 haplotype, three structural brain networks which subsume the identified cortical regions of interest (frontoparietal, dorsal-attention, and ventral-attention), and three cognitive indices (intelligence, attention, and immediate memory). Controls who were homozygous for the DRD2 major haplotype demonstrated greater cognitive performance as a result of dorsal-attention network mediation. However, this association was absent in the ‘at-risk’ group. This study provides the first evidence of a functional DRD2-brain-cognition pathway. The absence of typical brain-cognition relationships in young ‘at-risk’ individuals may reflect biological differences that precede illness onset. Further insight into early pathogenic processes may facilitate targeted early interventions.

双相情感障碍与认知缺陷和皮质变化有关，其发育动力学尚不清楚。多巴胺 D2 受体 ( DRD2 ) 基因与精神疾病和认知变异性有关。在这里，我们检查了大脑结构在DRD2基因组变异和认知表现之间的关系中的中介作用，根据与DRD2、双相情感障碍和/或先前文献中的认知相关的证据选择目标皮质区域。参与者（n = 143) 年龄在 12-30 岁之间，包括 62 名双相情感障碍患者的一级亲属（被视为“有风险”）、55 名对照和 26 名已确诊的双相情感障碍患者；所有人都是无关的高加索人，在三种所需的模式（结构磁共振成像、神经心理学和遗传数据）中拥有完整的数据。DRD2单倍型源自与可变剪接（即D2-短/-长同种型）相关的三个功能多态性（rs1800497、rs1076560、rs2283265）。适度的中介分析探讨了此DRD2之间关系的组差异单倍型，三个结构性脑网络，包含已识别的感兴趣的皮层区域（额顶、背侧注意和腹侧注意），以及三个认知指标（智力、注意力和即时记忆）。由于背侧注意网络介导， DRD2主要单倍型纯合子的对照组表现出更好的认知能力。然而，这种关联在“高危”组中不存在。该研究提供了功能性DRD2 - 大脑认知途径的第一个证据。年轻的“高危”个体缺乏典型的大脑认知关系可能反映了疾病发作之前的生物学差异。对早期致病过程的进一步了解可能有助于有针对性的早期干预。