The psychometric performance of the six-item FTND to assess physical dependence on tobacco smoking is well established, particularly items 1 and 4 which relate to heaviness of smoking [36],[37]. The significance levels of analyses of the association between individual FTND items and haplotypes are shown in Table 6 and positive scores on most items show a trend towards higher frequency of haplotype HA and a lower frequency of haplotype HC (Tables S5 and S6). Nominally significant results were obtained only for FTND item 4 (cigarettes per day) and FTND item 5 (smoking frequently during the first hours after waking). HA vs. HC associations with FTND items were tested within age of onset condition using chi-square for dichotomous items. For items 1 and 4, which have 4 ordered response options, Cochran's Test of Linear Trend was used to test the hypothesis that haplotype proportions change linearly across the response options. The only nominally significant results were obtained in the early onset condition for cigarettes per day (Item 4), Cochran's Test of Linear Trend (1, N = 1499) = 16.6, p<0.00005, and
