Associations Between Genetic Variation and Cigarette Smoking and Alcohol Drinking during Youth: Longitudinal Investigations

We evaluated genetic-based associations with early smoking and drinking behaviours among European-ancestry youth in a longitudinal cohort design. In Study 1, we examined associations between genetic variation in TAS2R38, which encodes a bitter taste receptor, and early smoking behaviours. Individuals with the PAV/PAV or PAV/AVI diplotypes (i.e., PAV diplotypes) are considered bitter tasters, whereas AVI/AVI (i.e., AVI diplotype) are non-tasters. Cox proportional hazards models estimated associations between TAS2R38 diplotype and time to early smoking outcomes in adolescent incident smokers (i.e., those who initiated smoking during study follow-up). While similar diplotype-based rates to first whole cigarette were found, those with the PAV diplotypes attained monthly smoking and converted to tobacco dependence (measured using three indicators ICD-10, mFTQ, and HONC) faster than those with the AVI diplotype. When these participants reached young adulthood (age 24), those with PAV diplotypes had higher mean cotinine + 3’hydroxycotinine, a biomarker of nicotine intake.In Study 2, we examined associations between genetic variation in fatty acid amide hydrolase (FAAH) and early drinking behaviours, and whether similar associations were observed with early smoking milestones. As part of the endocannabinoid system, which is implicated in psychiatric disorders and drug dependence, FAAH metabolizes endocannabinoids such as anandamide. Individuals with A-group genotypes (C/A or A/A) of a FAAH missense variant (rs324420; C>A) have slower enzymatic activity than those in the C-group (C/C genotype). We first replicated findings from two studies in adults, where those in the A-group had higher odds of past-year binge drinking at ages 20 and 30. Next, Cox proportional hazards models were used to estimate associations during adolescence, where those in the A-group had faster time to drinking initiation and daily drinking. Although the genotype associations extended to faster rates to smoking initiation, associations with early smoking milestones were inconsistent. Thus, the ability to taste bitter compounds increases the risk for early smoking behaviours, while slow FAAH activity increases risk for drug use initiation and harmful drinking behaviours. Our findings underscore the importance of examining genetic associations in acquisition and early drug use behaviours and contribute to our understanding of inter-individual differences in substance use in adolescence.

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