A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence

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. A meta-analysis was performed on two GWA studies of 1283 cases of alcohol dependence and 1416 controls in Caucasian populations. Through meta-analysis we identified 131 SNPs associated with alcohol dependence with p < 10⁻⁴. The best novel signal was rs6701037 (p = 1.86 × 10⁻⁷) at 1q24-q25 within KIAA0040 gene while the second best novel hit was rs1869324 (p = 4.71 × 10⁻⁷) at 2q22.1 within THSD7B. The third novel locus was NRD1 at 1p32.2 (the top SNP was rs2842576 with p = 7.90 × 10⁻⁶). We confirmed the association of PKNOX2 at 11q24.4 with alcohol dependence. The top hit of PKNOX2 (rs750338 with p = 1.47 × 10⁻⁶) in the meta-analysis was replicated with the Australian Twin-Family Study of 778 families (p = 1.39 × 10⁻²) Furthermore, several flanking SNPs of the top hits in the meta-analysis demonstrated borderline associations with alcohol dependence in the family sample (top SNPs were rs2269655, rs856613, and rs10496768 with p = 4.58 × 10⁻³, 2.1 × 10⁻⁴, and 2.86 × 10⁻³ for KIAA0040, NRD1 and THSD7B, respectively). In addition, ALK, CASC4, and SEMA5A were strongly associated with alcohol dependence (p < 2 × 10⁻⁵) in the meta-analysis. In conclusion, we identified three new loci (KIAA0040, THSD7B and NRD1) and confirmed the previous association of PKNOX2 with alcohol dependence. These findings offer the potential for new insights into the pathogenesis of alcohol dependence.