Abstract

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.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.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.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]).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.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.