Dissection of the Phenotypic and Genotypic Associations With Nicotinic Dependence

Abstract

Introduction: Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968, rs6474412, rs3733829, and rs1329650 in large-scale GenomeWide Association Studies. We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures. Methods:Four genetic variants were analyzed in 2,047 subjects of European descent (1,062 cases and 985 controls). Nicotine dependence was assessed with multiple smoking measures, including the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual for Mental Disorders-IV (DSM-IV) nicotine dependence, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives. Single-item measures of cigarettes per day (CPD) and time to first cigarette (TTF) in the morning were also examined.Results: Among the variants, association effect sizes were largest for rs16969968, with measures of craving and heavy smoking, especially cigarettes smoked per day, showing the largest effects. Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650. None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did CPD. Conclusions:CPD is an important simple measure that captures in part the genetic associations of CHRNA5 and nicotine dependence, even when other more comprehensive measures of smoking behaviors are examined. The CHRNA5 gene is associated with heavy compulsive smoking and craving; this should inform the mission to improve the diagnostic validity of DSM-V.

CHRNA5/A3/B4 Variant rs3743078 and Nicotine-Related Phenotypes: Indirect Effects Through Nicotine Craving

“…No previous study analyzed the association of the rs578776/rs3743078 locus with craving. One study showed an association of three related craving measures with CHR-NA5/A3/B4 variant rs16969968 (Chen et al, 2012), which is not consistent with our results showing no association. Another study showed an association of a craving scale with joint haplotypes of variants rs16969968 and rs578776, but only among early-onset smokers (Baker et al, 2009).…”

“…Although sample sizes were slightly different for the other CHRNA5/ A3/B4 variants (delineated below), demographic proportions were virtually the same. Lifetime smokers had smoked 100 cigarettes, a threshold widely used to indicate substantial smoking (Bondy et al, 2009;Chen et al, 2009Chen et al, , 2012Saccone et al, 2009aSaccone et al, , 2009b. Of these, 82.5% (n = 546) were male; 19.0% (n = 126) were 21-29 years old, 33.1% (n = 219) were 30-44, and 47.9% (n = 317) were 45 years or older; 28.8% (n = 191) were immigrants from the former Soviet Union.…”

“…However, little is known about the association of the two CHRNA5/A3/B4 loci with nicotine craving. One study showed an association of rs16969968 with three nicotine craving measures (Chen et al, 2012). Another study showed an association of craving with joint haplotypes of rs578776 and rs16969968, but only among early-onset smokers (Baker et al, 2009).…”

A Preliminary Exploration of College Smokers’ Reactions to Nicotine Dependence Genetic Susceptibility Feedback

“…Individuals with the risk allele for rs16969968 selfreport higher levels of nicotine dependence and report consuming more cigarettes per day. [24][25][26][27][28][29] In sum, feedback on genetic susceptibility to nicotine dependence can serve as a "teachable moment" acting as a warning sign to some college smokers, and as an indicator to others, that cessation is easier before addiction sets in. This approach may be most effective among light college smokers.…”

Examination of the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68) Factor Structure in a Sample of Pregnant Smokers

“…There is preliminary evidence that the WISDM PDM subscales are related to genetic variants located on CHRNA5-A3-B, which have been previously found to be associated with susceptibility for nicotine dependence. 7,30 Several studies have found mood and anxiety psychiatric diagnosis status to be related to the PDM composite scale and its subscales; and to theoretically relevant SDM subscales reflecting affective, cognitive enhancement, affiliative attachment, and lack of alternative reinforcer motives for smoking in pregnant and nonpregnant samples. [31][32][33][34][35] In a previous study that used the same sample as that of the current study, we found childhood trauma to be predictive of the PDM subscale of Tolerance and several SDM scales, with Negative Reinforcement having the greatest relative contribution to variance.…”