Our top GWAS hits replicated previous association signals for alcohol use traits. The strongest associations with AUDIT score in this study spanned the alcohol metabolism genes on chromosome 4q23 (10). Variants in this region were associated with AUDIT total score, AUDIT-C and AUDIT-P, demonstrating that alcohol metabolism is a risk factor for both alcohol consumption and problematic use. The second strongest signal, also associated with the three AUDIT phenotypes, is located in KLB, confirming the robust association of this gene with both alcohol consumption (9, 11, 12) in humans, and in mice (12). However, the biology of this locus could be more complex than previously described. Although the credible set analysis suggested that the more probable causal variants are all located on the first intron of KLB, one of these variants, rs11940694, is an eQTL for RFC1 expression in the brain, and S-PrediXcan analysis predicted that lower expression of RFC1 in the brain is associated with higher predicted AUDIT (AUDIT-C and AUDIT-P) scores. Interestingly, a gene in the complex GWAS signal on chromosome 19, Fibroblast growth factor 21 (FGF21), was
