Both GRM7 and GRM8 are part of the glutamate signaling pathway and were previously reported to be associated with nicotine dependence [30], [31] and smoking initiation [32] respectively. In addition, a genetic linkage peak near GRM7 and nominal association was reported for GRM7 and major depression in the OZALC-NAG heavy smoking families [33]. rs963843 (MAF = 0.14) in GRM8 was the most significant SNP for SAGE (p-value = 5.0E−3), with an increased number of CPD. Although not significant, we observed the same direction of effect for this SNP in both OZALC-NAG (p-value = 0.074) and ARIC (p-value = 0.10), with the combined p-value = 1.16E−3. Two additional SNPs, the protective rs1557644 (p-value = 3.0E−3; MAF = 0.35) and the risk rs1018854 (p-value = 3.27E−4; MAF = 0.44) were significant in OZALC-NAG and ARIC respectively. Moreover, the haplotype derived from the risk alleles showed a p-value = 5.40E−3 (effect = 0.21) for SAGE.
