In this study, we used a multi-omics integration approach to detect genes relevant to typical drinking (DPW) and AUD. The AUD GWAS meta-analysis used here specifically focused on the diagnosis rather than the disordered drinking. Importantly, our work highlights that GWAS variants for AUD and DPW are enriched in promoter regions of the fetal and adult brain. Using large-scale transcriptomic and epigenomic data from these tissues, we successfully fine mapped complex loci (17q.21.31, 11p11.2, 16p11.2) and identified likely functional variants and candidate causal genes associated with alcoholism. Prior transcriptomic data from human and animal brains highlighted the contribution of immune networks in drinking behaviors25–31. But these observations were never consistent with results from GWAS of AUD and DPW, most likely due to lack of power in these genomic studies. Transcriptomic changes can be either a cause or a consequence of chronic excessive alcohol consumption. The identification of genes and/ or pathways involved in immune signaling (SPI1, RXR activation), lipid metabolism (RXR and sulfotransferases), and regulation of alcohol metabolism (Sirutuin signaling) are therefore important as an attempt to fill gaps in our understanding of disease predisposition and underlying biological mechanisms in a genomic context.
