One limitation of the association tests is in the nicotine phenotype selection. It is known, for example, that variants within nicotinic receptor genes on chromosome 15 influence heaviness of smoking in smokers. Our nicotine dependence (exposed) phenotype is a measure of heaviness of smoking among individuals who have ever smoked, but the lowest p-value within nicotinic receptor genes was p=.01 for rs16969968, a variant known to be associated with heaviness of smoking in current smokers(21, 22). One possible explanation for our nonsignificant finding is that our exposure criteria were insufficient. This study did not ask, for example, whether an individual had ever smoked 100+ cigarettes, a common proxy for measures of lifetime regular smoking. An additional complication is that approximately half of the sample reported here is around 18 years old, and common SNPs in nicotinic receptor genes such as rs16969968 appear to influence smoking more strongly in older individuals(45, 46). It is also possible that we may have missed strong associations with nicotine dependence because we did not evaluate additional nicotine phenotypes due to our focus on the behavioral disinhibition hypothesis.
