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Objective: To clarify the nature of the association between dopamine genes and smoking by examining whether genetic variability in components of the dopamine pathway could explain refined phenotypes in adolescent smoking progression. Method: Data are from an ongoing prospective study of the long-term outcome of early risk factors studied since birth. At age 15 years, 220 participants (108 males, 112 females) completed a self-report questionnaire measuring smoking behavior and were genotyped for five dopamine gene variants. Results: Smoking initiation was related to allelic variation in the dopamine D-4 receptor gene (DRD4), whereas smoking continuation and dependence showed association with the dopamine D-2 receptor gene (DRD2). Adolescents with the seven-repeat allele of the common DRD4 exon 3 polymorphism had rates of ever smoking that were significantly higher than in those with other genotypes. Once smoking started, carriers of the T allele of a single nucleotide polymorphism of DRD2 (rs4648317) reported higher rates of current smoking and scored higher on nicotine dependence than their allelic counterparts. Among current smokers, intention to quit was significantly lower in adolescents homozygous for the 10-repeat allele of the common dopamine transporter 3 untranslated region polymorphism. Conclusions: Our results provide preliminary evidence of genetic influences on different stages of smoking and suggest the importance of specific dopamine genes in smoking progression in adolescence.
Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use
(2007)
Background: Recent animal research suggests that alterations in the corticotropin releasing hormone receptor 1 (CRHR1) may lead to heavy alcohol use following repeated stress. The aim of this study was to examine interactions between two haplotype-tagging single nucleotide polymorphisms (SNPs) covering the CRHR1 gene and adverse life events on heavy drinking in adolescents. Methods: Data were available from the Mannheim Study of Children at Risk, an ongoing cohort study of the long-term outcome of early risk factors followed since birth. At age 15 years, 280 participants (135 males, 145 females) completed a self-report questionnaire measuring alcohol use and were genotyped for two SNPs (rs242938, rs1876831) of CRHR1. Assessment of negative life events over the past three years was obtained by a standardized interview with the parents. Results: Adolescents homozygous for the C allele of rs1876831 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking in relation to negative life events than individuals carrying the T allele. No gene X environment interactions were found for regular drinking and between rs242938 and stressful life events. Conclusions: These findings provide first evidence in humans that the CRHR1 gene interacts with exposure to stressful life events to predict heavy alcohol use in adolescents.