To evaluate the significance of these CHRNA5-CHRNA3 single marker associations and the underlying haplotypes, five tagging SNPs capable of distinguishing these four haplotypes were assessed for association to FTND by age of daily smoking onset (daily smoking onset by vs. after age 16) in the combined UT-WI-LHS cohorts (total N = 2,827). Observed frequencies of Haplotypes A–D, respectively, by cohort were as follows: LHS, 39%, 37%, 19%, and 5%; UT, 38%, 38%, 20%, and 4%; and WI, 41%, 38%, 17%, and 4%. A test of all four haplotypes showed a significant omnibus association P value of 2.6×10−4 with high vs. low FTND score within the early onset group (Table 2), but not within the late onset group (P = 0.444). This omnibus haplotype test was supported by single marker association P values ranging from 1.1×10−3 to 1.7×10−4 (Figure 1). The main haplotype effect can be partitioned into two significant haplotype-specific associations (Table 2) with both a susceptibility effect for high dependence in the early onset group for haplotype HA (odds ratio (OR) 1.50, 95% CI 1.21 to 1.86, P =
