A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans

Abstract

Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.

Figure 1

CHRNA5 rs16969968 moderates the aversive effects of nicotine. The subjective aversive (a), pleasurable (b) and stimulatory (c) ratings of drug effects in response to doses of saline and nicotine for rs16969968*G homozygotes (n=133) and rs16969968*A carriers (n=59). The adjacent bar graphs show the change in response to nicotine relative to saline for each drug effect and each genotype group (GG, n=133; AG, n=53; AA, n=6). Mean values are presented (±SEM). 0.5 Nic=0.5 mg nicotine per 70 kg body weight and 1.0 Nic=1.0 mg nicotine per 70 kg body weight. ***P<5 × 10⁻⁸ for the interaction of genotype with dose.

Figure 2

CHRNA5 rs16969968*A carriers showed greater improvement in the Stroop Task. The throughput scores for (a) The Running Memory Continuous Performance Task (CP), (b) Mathematical Processing Task (MP), and (c) Stroop Task for rs16969968*G homozygotes and A carriers. Higher throughput scores indicate better performance, with possible scores ranging from 0 to 100 for all three tasks. The mean value adjusted for age, sex, and race is presented (±SEM), and the interactive effect of genotype with time point (baseline vs end of session) is shown. Main effects of genotype were not significant (P>0.3) for panels a, b and c. **P<0.005 for the interaction of genotype with time point.

Figure 3

The association of rs16969968 to nicotine withdrawal and the urge to smoke. (a) Minnesota Nicotine Withdrawal Scale (MNWS) scores and (b) Brief Questionnaire of Smoking Urges (BQSU) factor 1 (left) and factor 2 (right) scores, for rs16969968*G homozygotes and A carriers at baseline and at the end of the session. The mean value adjusted for age, sex, and race is presented (±SEM), and the interactive effect of genotype with time point (baseline vs end of session) is shown. The main effect of genotype was not significant for panels a or b. *P<0.05 and ^#P<0.1 for the interaction of genotype with time point.