One of the top-ranked SNPs was in the promoter region of BBX (Table 2); this SNP was also significant in the family sample, for both alcohol dependence and early onset (Table 2). Several additional SNPs just upstream of BBX were associated with both phenotypes in the GWAS (Supplementary Table 1). BBX is widely expressed in human tissues, and encodes the human homolog of Drosophila Bobbysox, an HMG-BOX transcription factor. The potential role of BBX in affecting risk for alcohol dependence is likely to be complex; BBX mRNA levels are themselves significantly increased by alcohol exposure (13% increase in lymphoblastoid cell lines, FDR = 9 × 10−5; Table 2). A SNP in intron 1 of KCNMA1 provided evidence in subjects of both European and African ancestry, and in the family sample (Table 2), KCNMA1 is expressed in brain, and encodes potassium large conductance calcium-activated channel, subfamily M, alpha member 1, a protein important in controlling neuronal excitability.
