Abstract
Background: Cigarette smoking is a costly and prevalent public health problem. Smoking behavior is under genetic influence and recent successes in genome-wide association studies (GWAS) of smoking quantity (cigarettes smoked/day) suggest opportunities to use genetic information to inform etiological and treatment research. GWAS samples consist of adult smokers and former smokers. A next step in translating GWAS discoveries into research tools is to test how GWAS-identified variation relates prospectively to the development of smoking behavior.
Methods: We used a genetic risk score (GRS) derived from smoking quantity results of 3 GWAS meta-analyses. We selected genome-wide significant single-nucleotide polymorphisms (SNPs) from regions replicated in 2 meta-analyses. The resulting 6-SNP score summarized smoking-associated variation around CHRNA5-CHRNA3-CHRNB4 and CYP2A6. We validated the GRS as a measure of heavy smoking risk in the Atherosclerosis Risk in the Communities Study European-descent sample (N = 8293). We then investigated prospective relationships between the GRS and developmental phenotypes of smoking behavior using the Dunedin Longitudinal Study, a birth cohort (n = 1037) followed through age 38 years (retention > 90%). We used smoking behavior data from 9 assessments spanning ages 11–38 years to follow individuals as they initiated smoking during adolescence, converted to daily smoking and progressed to heavy smoking during the teenage and young adult years, and as they developed nicotine dependence and struggled with cessation in their 20s and 30s.
Results: Individuals at high and low genetic risk initiated smoking around the same age and with similar frequency. Among initiates, individuals at higher genetic risk progressed more rapidly from smoking initiation to heavy smoking. This rapid progression was characterized by conversion to daily smoking as a teenager and progression to smoking > = 20 cigarettes/day by age 18 years. In turn, individuals at higher genetic risk developed more smoking problems as adults: they persisted longer in smoking heavily, developed more symptoms of nicotine dependence, and were more likely to fail in their cessation attempts. Further analysis revealed that faster progression from initiation to heavy smoking mediated genetic associations with adult smoking problems.
Conclusions: GWAS-identified variation in and around CHRNA5-CHRNA3-CHRNB4 and CYP2A6 influences the development of adult smoking problems partly by accelerating the developmental progression from smoking initiation to heavy smoking. Focusing on individual differences in smoking behavior following smoking initiation may help to identify causal variants in these genes. Public health initiatives that disrupt the developmental progression of smoking behavior, such as high surtaxes and age restrictions on tobacco sales, may ameliorate certain genetic risks for developing adult smoking problems.