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.