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 associated with AUDIT (AUDIT total score, AUDIT-C, AUDIT-P) at the gene-based level (Supplementary Table 17). FGF21 regulates sweet and alcohol preference in mice as part of a receptor complex with β-Klotho (KLB) in the central nervous system (33). Additionally, we replicated the association between rs1260326 in the gene GCKR and alcohol consumption (9, 11), here associated with AUDIT total score and AUDIT-C. Other loci previously associated with alcohol consumption include CADM2 (9), which was associated at the gene-based level for all three AUDIT traits. Here, the burden analysis suggests that multiple (rare and common) variants are necessary to explain the association signal. Intriguingly, several of the novel associations with AUDIT scores were mapped to highly pleiotropic genes (MAPT, FUT2, SLC39A8)(27).
