Previous studies have shown that PAU is a brain-related trait with evidence of functional and heritability enrichment in multiple brain regions. We performed gene-based association, TWAS in brain tissues, and H-MAGMA analysis in brain annotations. We identified 51 genes that were supported across multiple levels of analysis. For example, ADH1B expression in putamen was associated with PAU by TWAS, and with chromatin interaction in all 6 brain annotations by H-MAGMA, indicating additional potential biological mechanisms for the association of ADH1B with PAU risk through gene expression and/or chromatin interactions in brain, potentially independent of the well-known hepatic effect on alcohol metabolism. DRD2 expression in cerebellar hemisphere and chromatin interaction in all brain annotations were also associated with PAU risk. Alcohol metabolism, as is well reported, has effects that modulate alcohol’s aversive and reinforcing effects49, but also contributes to brain histone acetylation, gene expression and alcohol-related associative learning in mice50.
