FSTL4 and SEMA5A are associated with alcohol dependence: Meta-analysis of two genome-wide association studies

Background: Family, twin and adoption studies have clearly demonstrated that genetic factors are important in modulating the vulnerability to alcohol dependence. Several genome-wide association (GWA) studies of alcohol dependence have been conducted; however, few loci have been replicated. Methods: A meta-analysis was performed of two GWA studies of 1311 cases of alcohol dependence and 1418 controls in Caucasian populations. Replication of the top hits was attempted with the Australian Twin-Family Study of Alcohol Use Disorder dataset with 778 families. Results: Through meta-analysis we identified 81 SNPs associated with alcohol dependence with p < 10^-4. The best signal was rs930076 (p=3.86x10^-6) at 5p15.2 within SEMA5A gene while the second best hit was rs155581 (p=7.63x10^-6) at 5q31.1 within FSTL4. In addition, we confirmed the previously reported association of PKNOX2 at 11q24.3 with alcohol dependence (the top SNP is rs1426153 with p of 8.36x10^-6). The associations with the top SNPs were not replicated in the family sample; however, several flanking SNPs demonstrated borderline associations with alcohol dependence (top SNPs were rs950050 with p= 0.014, rs407758 with p=0.0066 and rs2509449 with p=0.0023 for SEMA5A, FSTL4 and PKNOX2, respectively). Conclusion: We identified two new loci (SEMA5A and FSTL4) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in alcohol dependence.