Genome-Wide and Candidate Gene Association Study of Cigarette Smoking Behaviors

Abstract

The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, ≤10 versus >10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10−7) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10−5 for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10−3), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4×10−5), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up.

MAO A VNTR polymorphism and amygdala volume in healthy subjects

“…However, recent methodological studies (Morey et al, 2009;Jovicich et al, 2009) have demonstrated that Freesurfer can be considered an acceptable substitute for manual tracing of automatically quantified amygdala volume, although a large cohort of subjects is warranted. Second, the lack of a significant association between amygdala volume and MAO A VNTR polymorphism could be influenced by further social/psychological variables not taken into consideration in this work, such as impulsivity (Soloff et al, 2008), social disadvantage experiences such as trauma or abuse history (Caspi et al 2002, Kim-Cohen et al 2006 or cigarette smoking behaviour (Caporaso et al, 2009) that could ultimately interact with MAO A functioning. In particular, the association between variants in MAO gene region and cigarette smoking behaviour is notable because of the role of the monoamine oxidases in the regulation of catecholamines and the inhibition of MAO A and B by tobacco smoke (Fowler et al, 2003).…”

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

“…Most prominent among these are the human genetic association studies showing that single nucleotide polymorphisms in the gene cluster CHRNA5/Α3/Β4, encoding for the α3, α5, and β4 nAChR subunits, are closely associated with the risk for heavy smoking, inability to quit, and increased sensitivity to nicotine. [7][8][9][10][11] Further, studies in knockout mice show that the β4 nAChR subunit is necessary for nicotine withdrawal because withdrawal is greatly diminished in β4 null mice, but not in β2 null mice. 12,13 Unlike the wide distribution of α4β2 nAChR in the brain, the α3 and β4 subunits are expressed in a restricted number of brain areas, mainly the medial habenula and interpeduncular nucleus, major cholinergic tracts in the brain that have recently garnered increasing attention for their involvement in various aspects of nicotine dependence.…”

The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

“…Another, not mutually exclusive, possibility is that individuals with one or more copies of the T-allele may be more resistant to the aversive side effects of nicotine (Munafo et al 2011). Interestingly, it is the T-allele of the rs1051730 polymorphism which has been repeatedly associated with nicotine dependence (Berrettini et al 2008;Bierut et al 2008;Caporaso et al 2009;Saccone et al 2009). Moreover, there is evidence for an association between the T-allele of the rs1051730 polymorphism and decreased likelihood of smoking cessation (Munafo et al 2011) -further emphasizing the role of the T-allele in the context of nicotine dependence and smoking behavior.…”

“…Moreover, our previous results indicate that there might be shared variance in the molecular genetic substrates for both nicotine dependence and sensorimotor gating: interestingly, the CHRNA3 rs1051730 T allele and the rs1317286 G allele have been firmly established as risk alleles for nicotine dependence (Berrettini et al 2008;Bierut et al 2008;Caporaso et al 2009;Saccone et al 2009). Probably, a genetically induced alteration in the nAChR-system is (in part) responsible for both deficits in sensorimotor gating and increased risk for smoking.…”