Significant association was also detected with QUANTDEP for the SNP rs2567261 in ARHGAP28 (p=3.8×10−8). Further evidence of association was observed with both genotyped and imputed SNPs within the gene. ARHGAP28 is also known as Rho GTPase activating protein 28. GTPase-activating proteins target GTPases, and are mediated by exposure to alcohol, cannabis, cocaine, and opioids. For example Rho1 and Rac moderate the stimulating and sedative effects of acute ethanol intoxication in Drosophila (Rothenfluh et al., 2006). Thus, there is strong biological rationale for this gene as a potential candidate for substance dependence. Of note, this SNP was modestly associated with ANYDEP (p=3.2×10−4) in this sample and with previously published alcohol symptom count in the COGA family sample (p=8.7×10−5). However, rs2567261 was not significantly associated with alcohol symptom count in the SAGE sample, although there was a trend in that direction (p=0.08) (Wang et al., 2013). Although the association did not replicate in the SAGE sample for this phenotype, there was a trend towards association with the other phenotype, ANYDEP (p=0.08). This weak replication for a different phenotype may be due to
