CHRNB3 is more strongly associated with Fagerström Test for Cigarette Dependence-based nicotine dependence than cigarettes per day: Phenotype definition changes genome-wide association studies results

Aims: Nicotine 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. Design: Genome-wide association study. Setting: Community sample. Participants: A 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. Measurements: Nicotine dependence defined by FTCD score ≥4, CPD. Findings: The 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). Conclusions: Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci.