Association of specific haplotypes of neurotrophic tyrosine kinase receptor 2 gene (NTRK2) with vulnerability to nicotine dependence in African-Americans and European-Americans

Background: The gene encoding neurotrophic tyrosine kinase receptor 2 (NTRK2) has been localized to a region on chromosome 9q22-q23 that showed a suggestive linkage to nicotine dependence (ND) in our previous linkage analyses. However, no association of NTRK2 with ND has been identified. Methods: Family-based association analyses of 2037 participants (1366 African Americans [AA], 671 European Americans [EA]) representing 602 nuclear families were performed to evaluate association of nine single nucleotide polymorphisms (SNPs) within NTRK2 with ND. Results: Individual SNP-based association analysis indicated that in the EA sample, SNPs rs1659400 and rs1187272 were significantly associated with at least one adjusted ND measure. Haplotype analysis revealed that even after Bonferroni correction, the baplotype T-T-A of rs1659400-rs1187272-rs1122530 bad a highly significant positive association, with adjusted ND measures in the EA sample (max Z = 3.78, p =. 0001, frequency 59.9%). We further identified a major baplotype, T-G-C-A-A (26%), formed by rs993315-rs736744-rs920776-rs4O75274-rs729560, which showed a significant positive association (max Z = 2.97, p=.003) with adjusted ND measures in the AA sample. Conclusions: These results strongly suggest that NTRK2 is a susceptibility gene for ND. These findings imply that NTRK2 plays a role in the etiology of ND and represents an important biological candidate for further investigation.