Importance Past studies have identified associations between brain macrostructure and alcohol use behaviors. However, identifying directional associations between these phenotypes is difficult due to the limitations of observational studies. Objective To use mendelian randomization (MR) to identify directional associations between brain structure and alcohol use and elucidate the transcriptomic and cellular underpinnings of identified associations. Design, Setting, and Participants The main source data comprised summary statistics from population-based and case-control genome-wide association studies (GWAS) of neuroimaging, behavioral, and clinical phenotypes (N = 763 874). Using these data, bidirectional and multivariable MR was performed analyzing associations between brain macrostructure and alcohol use. Downstream transcriptome-wide association studies (TWAS) and cell-type enrichment analyses investigated the biology underlying identified associations. The study approach was data driven and did not test any a priori hypotheses. Data were analyzed August 2021 to May 2022. Main Outcomes and Measures Brain structure phenotypes (global cortical thickness [GCT] and global cortical surface area [GCSA] in 33 709 individuals and left-right subcortical volumes in 19 629 individuals) and alcohol use behaviors (alcoholic drinks per week [DPW] in 537 349 individuals, binge drinking frequency in 143 685 individuals, and alcohol use disorder in 8845 individuals vs 20 657 control individuals [total of 29 502]). Results The main bidirectional MR analyses were performed in samples totaling 763 874 individuals, among whom more than 94% were of European ancestry, 52% to 54% were female, and the mean cohort ages were 40 to 63 years. Negative associations were identified between genetically predicted GCT and binge drinking (β, -2.52; 95% CI, -4.13 to -0.91) and DPW (β, -0.88; 95% CI, -1.37 to -0.40) at a false discovery rate (FDR) of 0.05. These associations remained significant in multivariable MR models that accounted for neuropsychiatric phenotypes, substance use, trauma, and neurodegeneration. TWAS of GCT and alcohol use behaviors identified 5 genes at the 17q21.31 locus oppositely associated with GCT and binge drinking or DPW (FDR = 0.05). Cell-type enrichment analyses implicated glutamatergic cortical neurons in alcohol use behaviors. Conclusions and Relevance The findings in this study show that the associations between GCT and alcohol use may reflect a predispositional influence of GCT and that 17q21.31 genes and glutamatergic cortical neurons may play a role in this association. While replication studies are needed, these findings should enhance the understanding of associations between brain structure and alcohol use.

中文翻译：

---

成人大脑结构与酒精使用行为之间的关联：孟德尔随机化和多组学研究。

重要性 过去的研究已经确定了大脑宏观结构与酒精使用行为之间的关联。然而，由于观察性研究的局限性，很难确定这些表型之间的方向关联。目的使用孟德尔随机化（MR）来识别大脑结构和酒精使用之间的方向关联，并阐明所识别关联的转录组和细胞基础。设计、设置和参与者 主要来源数据包括来自神经影像学、行为学和临床表型的基于人群和病例对照全基因组关联研究 (GWAS) 的汇总统计数据 (N = 763 874)。使用这些数据，进行双向和多变量 MR，分析大脑宏观结构与酒精使用之间的关联。下游转录组关联研究 (TWAS) 和细胞类型富集分析调查了已确定关联的生物学基础。该研究方法是数据驱动的，没有测试任何先验假设。数据分析时间为 2021 年 8 月至 2022 年 5 月。主要结果和测量 脑结构表型（33 709 人的全球皮质厚度 [GCT] 和全球皮质表面积 [GCSA] 和 19 629 人的左右皮质下体积）和酒精使用行为（537 349 人每周饮酒 [DPW]，143 685 人暴饮暴食，8845 人有酒精使用障碍，对照组为 20 657 人[总计 29 502]）。结果 主要的双向 MR 分析在总共 763 874 人的样本中进行，其中超过 94% 是欧洲血统，52% 至 54% 为女性，平均队列年龄为 40 至 63 岁。在基因预测的 GCT 和暴饮暴食（β，-2.52；95% CI，-4.13 至 -0.91）和 DPW（β，-0.88；95% CI，-1.37 至 -0.40）之间以错误的发现率确定了负相关(FDR) 为 0.05。这些关联在考虑神经精神表型、物质使用、创伤和神经退行性变的多变量 MR 模型中仍然显着。GCT 和酒精使用行为的 TWAS 在 17q21.31 基因座上确定了 5 个与 GCT 和暴饮或 DPW 相关的基因（FDR = 0.05）。细胞类型富集分析表明谷氨酸能皮质神经元与酒精使用行为有关。结论和相关性 本研究的结果表明，GCT 与酒精使用之间的关联可能反映了 GCT 的易感性影响，并且 17q21.31 基因和谷氨酸能皮质神经元可能在这种关联中起作用。虽然需要进行复制研究，但这些发现应该会增强对大脑结构与酒精使用之间关联的理解。