AbstractAimsNicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta‐analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome‐wide association studies of nicotine dependence.DesignGenome‐wide association study.SettingCommunity sample.ParticipantsA total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans.MeasurementsNicotine dependence defined by FTCD score ≥4, CPD.FindingsThe genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR) = 0.65, P = 2.4 × 10−8]. This association was further strengthened in a meta‐analysis with a previously published data set (combined P = 6.7 × 10−16, total n = 4200). When CPD was used as an alternate phenotype, the association no longer reached genome‐wide significance (β = −0.08, P = 0.0004).ConclusionsDaily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci.