Glutamatergic cortical neurons and 17q21.31 genes may be integral in the association between global cortical thickness (GCT) and alcohol use in adults, according to study findings published in Journal of the American Medical Association Psychiatry.
Researchers conducted a Mendelian randomization (MR) study to analyze associations between brain macrostructure and alcohol use. They included data from 763,874 participants from population-based and case-control genome-wide association studies (GWAS) of behavioral, neuroimaging, and clinical phenotypes. GWAS data was extracted from participants in the UK Biobank, Enhancing Neuro-Imaging Genetics through Meta Analysis, Psychiatric Genomics Consortium, and GWAS & Sequencing Consortium of Alcohol and Nicotine use studies.
The biology underlying the associations between brain macrostructure and alcohol use was examined with cell-type enrichment analyses and downstream transcriptome-wide association studies (TWAS). They analyzed data on GCT and global cortical surface area (n=33,709), alcoholic drinks per week (n=537,349), left-right subcortical volumes (n=19,629), binge drinking frequency (n=143,685), and individuals with alcohol use disorder (AUD; n=8845) vs control participants (n=20,657).
Among the bidirectional MR analyses of 763,874 participants, (>94% European; 53% women; mean age, 40-63 years) there were negative associations between genetically predicted GCT and binge drinking (β, -2.52; 95% CI, -4.13 to -0.91) and drinks per week (β, -0.88; 95% CI, -1.37 to -0.40) at a false discovery rate (FDR) of 0.05. These associations were unidirectional. These associations remained significant in multivariable MR models accounting for trauma, neurodegeneration, substance use, and neuropsychiatric phenotypes.
In tests of left-right subcortical volumes on alcohol behaviors, the researchers observed a unidirectional association between greater right pallidum volume and increased binge drinking, and greater risk for AUD. Genetically predicted right pallidum volume was nominally associated with AUD and binge drinking. There were nominally significant unidirectional associations between left pallidum and binge drinking, brain stem with binge drinking, and brain stem with AUD.
Nominally significant unidirectional associations between binge drinking and right amygdala volume, and between AUD and right putamen volume were observed.
Five genes at the 17q21.31 locus were oppositely associated with GCT and binge drinking or drinks per week (FDR =0.05) from TWAS of GCT and alcohol use behaviors. Glutamatergic cortical neurons were found to be implicated in alcohol use behaviors according to cell-type enrichment analyses. MR analysis did not find any nominally significant associations between GCT and genetically predicted alcohol use.
Limitations of the study include the possibility of weak MR instrumentation bias, increase in horizontal pleiotropy, confounding or mediating traits, and the fact that the neuroanatomical phenotypes analyzed may not fully encapsulate brain damage.
Study authors conclude that the most robust finding was an association between alcohol use and genetically predicted GCT. They add, “[T]he 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.”
Mavromatis LA, Rosoff DB, Cupertino RB, Garavan H, Mackey S, Lohoff FW. Association between brain structure and alcohol use behaviors in adults: a mendelian randomization and multiomics study. JAMA Psychiatry. Published online September 1, 2022. doi:10.1001/jamapsychiatry.2022.2196