risk LD blocks, which were not observed in the present study. Second, most replicable risk SNPs in this block had strong cis-acting regulatory effects on PHF3-PTP4A1 mRNA expression. This increased the possibility that PHF3-PTP4A1 per se played a direct functional role in the disorder. Third, many PHF3-PTP4A1 SNPs had significant (in PHF3) or slight (in PTP4A1) potential for altering the secondary RNA structure (predicted by MFOLD [23]) (Table S4), providing additional evidence in support of the hypothesis that PHF3-PTPA41 per se contributed to alcohol dependence. Fourth, distributions of −log(P) values for gene-disease associations and for gene-expression associations were highly consistent across at least six populations. This might suggest that the majority of the functions of PHF3-PTP4A1 contributed to the risk for alcohol dependence, and that the regulatory pathway via which these SNPs caused alcohol dependence might be related to the PHF3 and PTP4A1 proteins per se. Taken together, these findings strongly supported the hypothesis that PHF3-PTP4A1 harbored a causal locus for alcohol dependence.
