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.
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Acknowledgements
We thank the individuals and families participating in this work and the interviewers at all the participating sites for collecting the data. This study was supported by NIH Grants R01 DA12690, R01 DA12849, and R01 AA11330.
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Dr Kranzler has received consulting fees from Alkermes, GlaxoSmithKline, Gilead, and Lundbeck and research support from Merck. Dr Anton reports for the last 2 years, being a consultant for Eli Lilly, GlaxoSmithKline, and Alkermes. Drs Kranzler and Anton also report associations with Eli Lilly, Merck, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and they receive support from ACTIVE. Dr Gelernter reports that he has received compensation for professional services in the previous 3 years from the following entities: Yale University School of Medicine, Veterans Affairs Healthcare System (VA), and the National Institutes of Health (NIAAA, NIDA, and NIMH), and related to academic lectures and editorial functions in various scientific venues (including the ACNP). The other authors declared no conflict of interest.
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Xie, P., Kranzler, H., Zhang, H. et al. Childhood Adversity Increases Risk for Nicotine Dependence and Interacts with α5 Nicotinic Acetylcholine Receptor Genotype Specifically in Males. Neuropsychopharmacol 37, 669–676 (2012). https://doi.org/10.1038/npp.2011.240
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DOI: https://doi.org/10.1038/npp.2011.240
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