ABSTRACT Background Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors and/or causal consequences of alcohol use remains poorly understood. Methods Data came from 3 neuroimaging samples (total n=2,423), spanning childhood/adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use, and/or a causal consequence of alcohol use. Finally, we evaluated whether GWAS-defined genomic risk for alcohol consumption is enriched for genes preferentially expressed in regions identified in our neuroimaging analyses, using heritability and gene-set enrichment, and transcriptome-wide association study (TWAS) approaches. Results Smaller right dorsolateral prefrontal cortex (DLPFC; i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene-sets preferentially expressed in the DLPFC and associated with differential expression of C16orf93 , CWF19L1 , and C18orf8 in the DLPFC. Conclusions These data suggest that smaller DLPFC and insula GMV plausibly represent predispositional risk factors for, as opposed to consequences of, alcohol use. Alcohol use, particularly when heavy, may potentiate these predispositional risk factors. DLPFC and insula GMV represent promising biomarkers for alcohol consumption liability and related psychiatric and behavioral phenotypes.

Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption