Also, our trait of interest was FTND as an ordinal trait, whereas the strongest reported chromosome 15 cluster associations have been for smoking quantity or closely related traits. For example, in a study of >8000 Finnish subjects, each risk allele at CHRNA5*rs16969968 corresponded to about one additional cigarette smoked per day (33). Similar smoking quantity-based findings have emerged (34), including from large meta-analyses (11–13,35). Although one item in the FTND assesses smoking quantity (7) and contributes to the overall score, it is not a distinctive or predominant component of the assessment. Although CHRNA5-CHRNA3-CHRNB4 candidate SNPs have also been associated with ND based on dichotomized FTND scores (36), the results fell just short of the GWAS threshold of 5 × 10−8. Thus, the explanation for our lack of observation of significant associations to this cluster could also be our phenotype, i.e., FTND, as an ordinal trait.
