Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women

Abstract

Background Tobacco smoking is the leading preventable cause of death in the developed world. Identifying risk factors for smoking may lead to more effective treatments. Genome wide association studies revealed a relationship between development of nicotine dependence and a single-nucleotide polymorphism (SNP, rs16969968) of the nicotine acetylcholine receptor (nAChR) alpha-5 subunit gene (CHRNA5). The relationship between this SNP and other factors contributing to smoking behavior such as smoking cue reactivity is unclear. Methods We assessed the role of rs16969968 on brain functional MRI (fMRI) reactivity to smoking cues by studying nicotine dependent women with the nicotine dependence ‘risk’ allele (A allele, N=14) and without the ‘risk’ allele (G/G smokers, N=10). Nicotine dependence severity, as assessed with the Fagerstrom test for nicotine dependence, smoking pack-years, and expired carbon monoxide levels, were equivalent in these groups. Results We observed a group difference in fMRI reactivity; women without the A allele (G/G smokers) showed greater fMRI reactivity to smoking images in brain areas related to memory and habitual behavior such as the hippocampus and dorsal striatum. Conclusions Our finding suggests that nicotine-dependent smokers lacking the rs16969968 A allele are more likely to recall smoking-related memories and engage in habitual responding to smoking cues than A allele smokers. Although more studies are necessary to determine the mechanism underlying and significance of this cue reactivity difference, these data suggest that smokers may develop and remain nicotine dependent due to different factors including genetics and cue reactivity. This finding may have implications for personalizing smoking treatment.

Multi-site exploration of sex differences in brain reactivity to smoking cues: Consensus across sites and methodologies

“…In evaluating the sexes individually, we also replicated the finding of high SC reactivity in men (Wetherill et al, 2013), but failed to find any significant SC-related activation in women. This is inconsistent with our prior studies showing heightened SC-induced brain reactivity in women (Janes et al, 2009, 2010, 2012; Wetherill et al, 2013). However, this variability is consistent with the idea that circulating gonadal hormones in women impact women’s responses to SCs potentially leading to variability across studies (Franklin et al, 2015; Mendrek et al, 2014; for review see Wetherill et al, 2016).…”

The Genetics, Neurogenetics and Pharmacogenetics of Addiction

“…Given these differential associations with lifetime and immediate smoking, and the extant literature demonstrating the independence of their effects, the authors posit that rs16969968 and rs578776 genotypes contribute to trait and state aspects of smoking respectively [99]. In contrast to the study by Janes and colleagues [100], the results of this study suggest that CHRNA5-A3-B4 genetic risk covaries with corticostriatal correlates of smoking.…”

Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence

“…In smokers who carry this CHRNA5 risk allele, compared with noncarriers, nicotine seeking through PF is increased, namely through withdrawal avoidance, whereas susceptibility to NPF, in particular cue-induced craving (Janes et al, 2012), is decreased. This supports the notion that the two types of factors (PF/NPF) can vary independently.…”