A SNP (rs10893366), in PKNOX2 (p < 10–7) was also reported by Bierut et al. (2010). While subsequent GWAS identified the same SNP (rs10893366) (p < 10–6) (Zuo et al., 2012), as well as two different SNPs (rs750338 and rs1426153) (p < 10–6) in PKNOX2 associated with alcohol dependence, which strongly supports a critical role of this gene in addiction (Table 3). How might genetic variation in PKNOX2 alter cellular function underlying alcohol dependence phenotypes? PBX/Knotted 1 Homeobox 2 (PKNOX2) belongs to the TALE (3-amino acid loop extension) class of homeodomain proteins characterized by a 3-amino acid extension between alpha helices 1 and 2 within the homeodomain (Imoto et al., 2001) (Fig. 1 and Table 3). PKNOX2 can function as a nuclear transcription factor that regulates gene expression by binding to DNA in a sequence-specific manner to unique DNA recognition motifs (Fognani et al., 2002). There is also concordance between rodents and humans for a role of PKNOX2 in alcohol-related phenotypes. A massive brain transcriptome study of gene expression alterations in rodents that display an innate tendency for a high
