Impaired cognitive control has been implicated in cocaine use disorder (CUD). GABAergic treatments have been proposed for CUD. Here we examined relationships between GABAergic genes and neural correlates of cognitive control in CUD. We analyzed two independent African American cohorts: one of >3,000 genomewide-genotyped subjects with substance dependence and another of 40 CUD and 22 healthy control (HC) subjects who were exome-array genotyped and completed an fMRI Stroop task. We used five association thresholds to select variants in the reference cohort, yielding five polygenic risk scores (i.e., CUD-GABA-PRSs) for the fMRI cohort. At p<0.005, the CUD-GABA-PRSs, which aggregated relative risks of CUD from 89 variants harboring in 16 genes, differed between CUD and HC individuals in the fMRI sample (p=0.013). This CUD-GABA-PRS correlated inversely with Stroop-related activity in the left precuneus in CUD (r=-0.58, p_FWE<0.05) but not HC participants. Post-hoc seed-based connectivity analysis of the left precuneus identified reduced functional connectivity to the posterior cingulate cortex (PCC) in CUD compared to HC subjects (p=0.0062) and the degree of connectivity correlated with CUD-GABA-PRSs in CUD individuals (r=0.287, p=0.036). Our findings suggest that the GABAergic genetic risk of CUD in African Americans relates to precuneus/PCC functional connectivity during cognitive control. Identification of these GABAergic processes may be relevant targets in CUD treatment. The novel identification of 16 GABAergic genes may be investigated further to inform treatment development efforts for this condition that currently has no medication with a formal indication for its treatment.

认知控制受损与可卡因使用障碍（CUD）有关。GABAergic 治疗已被提议用于 CUD。在这里，我们检查了 GABA 能基因与 CUD 中认知控制的神经相关性之间的关系。我们分析了两个独立的非裔美国人队列：其中一个是 >3,000 名具有物质依赖的全基因组基因分型受试者，另一个是 40 名 CUD 和 22 名健康对照 (HC) 受试者，他们进行了外显子组阵列基因分型并完成了 fMRI Stroop 任务。我们使用五个关联阈值来选择参考队列中的变体，为 fMRI 队列产生五个多基因风险评分（即 CUD-GABA-PRS）。在p <0.005 时，CUD-GABA-PRS 汇总了来自 16 个基因的 89 个变体的 CUD 相对风险，在 fMRI 样本中的 CUD 和 HC 个体之间存在差异。p = 0.013)。这种 CUD-GABA-PRS 与 CUD 中左楔前叶的 Stroop 相关活动呈负相关（r =-0.58，p _FWE <0.05），但与 HC 参与者无关。与 HC 受试者相比，左楔前叶的事后基于种子的连接性分析发现 CUD 中与后扣带皮层 (PCC) 的功能连接性降低 ( p = 0.0062)，并且连接性程度与 CUD 个体中的 CUD-GABA-PRS 相关( r =0.287, p= 0.036）。我们的研究结果表明，非洲裔美国人 CUD 的 GABAergic 遗传风险与认知控制期间的楔前叶/PCC 功能连接有关。这些 GABA 能过程的识别可能是 CUD 治疗中的相关目标。可以进一步研究对 16 个 GABAergic 基因的新鉴定，为目前尚无正式治疗适应症药物的这种疾病的治疗开发工作提供信息。