Beyond the alcohol metabolizing genes, the region containing the genes beta-klotho (KLB) and the Fibroblast growth factor 21 (FGF21) has been robustly associated with alcohol consumption. The AlcGen consortium was the first to show that the A allele of rs11940694 (Figure 2), located in the intron of KLB, was associated with reduced alcohol consumption (15). This finding has since been replicated (Table 1) - the same SNP was associated with alcohol consumption (17, 18, 22, 23) and alcohol misuse (22). Beta-klotho is a transmembrane protein that acts as a cofactor for the circulating hormone fibroblast growth factor 21 (FGF21) by facilitating its binding to FGF receptors (FGFR). Interestingly the FGF21 gene, which is located on chromosome 19, was also associated with AUDIT scores at the gene-level in humans (22). Beta-klotho is primarily expressed in the liver, adipose tissue and pancreas (26), and recent studies have shown that it regulates brain specific functions related to alcohol consumption in mice. For example, mice lacking brain expressed Klb showed increased ethanol preference (15). Furthermore, FGF21 was found to suppress ethanol consumption in wild-type
