Up to date, most of the genetic studies on smoking have focused on adulthood and little is known about genetic factors influencing smoking in adolescence, which is a critical period for smoking initiation(30, 31). Aproximately 80–90% of adult-smokers initiate use before age 18 years(31) and ~40% before age 14(32). Early initiation (before age 16 years) of tobacco use is associated with increased risk of developing nicotine(33, 34) and other drug dependencies(35–37). Genetic influences moderating smoking behaviour are likely to vary both quantitatively and qualitatively during the lifespan(38) and most of the studies performed so far have not tested for developmental changes in gene effects. Finally, although several whole genome association studies on smoking have been performed on very large study samples, these studies have not taken into account gene-gene and gene-environment interplays. In the present study, we tested the independent and combined effects of common polymorphisms within CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters on smoking behaviour during adolescence and mid-adulthood in a prospective general population based cohort including 4,762 Finns (Northern Finland 1966 Birth Cohort, NFBC 1966). We tested whether the genetic
