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.
paper
Primary
Public
- Authors
- Rice, John P; Hartz, Sarah M; Agrawal, Arpana; Almasy, Laura; Bennett, Siiri; Breslau, Naomi; Bucholz, Kathleen K; Doheny, Kimberly F; Edenberg, Howard J; Goate, Alison M; Hesselbrock, Victor; Howells, William B; Johnson, Eric O; Kramer, John; Krueger, Robert F; Kuperman, Samuel; Laurie, Cathy; Manolio, Teri A; Neuman, Rosalind J; Nurnberger, John I; Porjesz, Bernice; Pugh, Elizabeth; Ramos, Erin M; Saccone, Nancy; Saccone, Scott; Schuckit, Marc; Bierut, Laura J; GENEVA Consortium
- Year
- 2012
- Journal
- Addiction (Abingdon, England)
- PMID
- 22524403
- DOI
- 10.1111/j.1360-0443.2012.03922.x
- PMCID
- PMC3427406
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.
Manhattan plot of p-values from multivariate logistic regression models testing for association with cigarettes per day (a) and nicotine dependence (b).
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