Positive associations between variation in TTC12-ANKK1-DRD2 and smoking have been already reported(8, 11, 12, 19, 20). In our study, the most significantly associated allele was rs10502172[G] mapping in TTC12. Additional alleles that were significantly overrepresented in smokers than non-smokers, were ANKK1-rs2734849[A] and TTC12-rs2303380[G]. The same alleles at these two loci were associated with nicotine dependence in two previous studies(11, 12). Haplotype-analyses were conducted to help narrow the location of a susceptibility locus, although the high linkage disequilibrium across the entire region limits the possibility to exactly localize the association signal. A protective haplotype, namely AAGGGAAAAGGGACGGGA, spanning block-two, was significantly associated with smoking. Interestingly, haplotype GGGGAGGGAGAGGCGGGA, which shares the same allelic configuration as AAGGGAAAAGGGACGGGA at the last five markers, was found to have the same frequency in smokers and non-smokers. This result indicates that the potential ‘causal locus’ might map within the first part of block-two that covers the 3′ region of TTC12, ANKK1, and the 5′ region of DRD2. A possible functional locus here is rs2734849, a missense variation leading to a Histidine to Arginine substitution at codon 490 of the ANKK1 gene that appears to be involved in regulation of DRD2 expression(11).
