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Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. Data Sources: Primary data. Study Selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DataExtraction: Uniform statistical analysis scripts were runlocally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD <= 10) with age-at-onset information, re-ducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset <= 16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with ther s16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. Data Synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36-1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR=1.27; 95% CI, 1.21-1.33, n=19 505) (P=.01). Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers
