Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior
Copyright policy )Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior
Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
- University of Queensland Australia
- Gentofte Hospital Denmark
- Amsterdam UMC Netherlands
- University of Copenhagen Denmark
- Erasmus University Rotterdam Netherlands
Netherlands Twin Register (NTR), Male, EMC NIHES-01-64-01, Lung Neoplasms, EMC NIHES-01-64-02, 610, Receptors, Nicotinic, Nicotinic, IGMD 6: Hormonal regulation, Cohort Studies, Cytochrome P-450 CYP2A6, 1311 Genetics, SDG 3 - Good Health and Well-being, Receptors, 616, Odds Ratio, Humans, NCEBP 2: Evaluation of complex medical interventions, Internal Medicine - Radboud University Medical Center, EMC MGC-02-96-01, Alleles, Genome-wide association, Smoking, Genetic Variation, Susceptibility locus, Genomics, Tobacco Use Disorder, NCEBP 1: Molecular epidemiology, ONCOL 5: Aetiology, screening and detection, EMC MM-01-39-02, Phenotype, genome-wide association nicotinic acetylcholine-receptors lung-cancer susceptibility locus molecular-genetics heavy smoking adult twins dependence genes snps, Nicotinic acetylcholine-receptors, Female, Aryl Hydrocarbon Hydroxylases, Lung-cancer, Genome-Wide Association Study
Netherlands Twin Register (NTR), Male, EMC NIHES-01-64-01, Lung Neoplasms, EMC NIHES-01-64-02, 610, Receptors, Nicotinic, Nicotinic, IGMD 6: Hormonal regulation, Cohort Studies, Cytochrome P-450 CYP2A6, 1311 Genetics, SDG 3 - Good Health and Well-being, Receptors, 616, Odds Ratio, Humans, NCEBP 2: Evaluation of complex medical interventions, Internal Medicine - Radboud University Medical Center, EMC MGC-02-96-01, Alleles, Genome-wide association, Smoking, Genetic Variation, Susceptibility locus, Genomics, Tobacco Use Disorder, NCEBP 1: Molecular epidemiology, ONCOL 5: Aetiology, screening and detection, EMC MM-01-39-02, Phenotype, genome-wide association nicotinic acetylcholine-receptors lung-cancer susceptibility locus molecular-genetics heavy smoking adult twins dependence genes snps, Nicotinic acetylcholine-receptors, Female, Aryl Hydrocarbon Hydroxylases, Lung-cancer, Genome-Wide Association Study
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