Childhood adversity increases risk for nicotine dependence and interacts with α5 nicotinic acetylcholine receptor genotype specifically in males

Abstract

The relative importance of specific genetic and environmental factors in regulating nicotine dependence (ND) risk, including the effects on specific forms of childhood adversity on smoking risk, have been understudied. Genome-wide association studies and rodent models have demonstrated that the α5 nicotinic acetylcholine receptor gene (CHRNA5) is important in regulating nicotine intake. Childhood adversity increases the methylation level of the CHRNA5 promoter region in European Americans (EAs), an effect that was observed only in males (Zhang et al, submitted for publication). In view of this potential sex difference in the effects of early life experience on smoking, we investigated the presence of a sex-specific gene-by-environment effect of this marker on ND risk. A nonsynonymous SNP in CHRNA5 previously associated to ND and several related traits, rs16969968, was genotyped in 2206 EAs (1301 men and 905 women). The main and interactive effects of childhood adversity and rs16969968 genotype on diagnosis of ND and ND defined by dichotomized Fagerstrom test for ND (FTND) scores were explored. Men and women were analyzed separately to test for sex differences. Childhood adversity significantly increased ND risk in both sexes, and the effect in women was twice than that in men. Significant interactive effects of childhood adversity and rs16969968 genotype were observed in men (ND: OR=1.80, 95% CI=1.18-2.73, P=0.0044; FTND: OR=1.79, 95% CI=1.11-2.88, P=0.012). No interaction was found in women. This study provides evidence of a sex-specific gene × environment effect of CHRNA5 and childhood adversity on the risk for ND.

Figure 1

Cumulative association of numbers of categories of childhood adversity experienced and rate of nicotine dependence diagnosis in men and women. The number of subjects with nicotine dependence and the total number of participants in each group are shown for each level of childhood adversity.

Figure 2

rs16969968 genotype interacted with childhood adversity to modify risk for the diagnosis of nicotine dependence in EA men (a), but not in EA women (b). The number of subjects with nicotine dependence and the total number of participants in each group are shown. Men homozygous for the A allele had the highest risk of nicotine dependence when exposed to childhood adversity.