Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program

Objective Existing genetic studies of nicotine consumption have largely focused on cigarette smoking. Different modes of nicotine use have varying use patterns and user characteristics that may reflect distinct environmental and genetic influences. This study aims to identify the shared and specific genetic risks for five nicotine use modes. Methods We performed a common variant multi-ancestral genome-wide association study (cross-ancestry N = 304,213) of five types of nicotine use in the All of Us Research Program: lifetime use of electronic nicotine (e-nicotine) products, cigars, tobacco in a hookah, smokeless tobacco, or at least 100 cigarettes. Results Nicotine users, regardless of mode, were more likely to be male and of younger age (except for cigarette use), and all modes of use were positively associated with tobacco use disorder diagnoses. GWAS meta-analyses of cigarette, e-nicotine, cigar, and smokeless tobacco use identified 87, 4, 1, and 1 genome-wide risk loci, respectively (none for hookah), including previously identified genes (e.g., CHRNA4 for cigarettes). Cigarette, e-nicotine, and smokeless tobacco use showed strong genetic correlations (rg=0.82-0.92), while cigar and hookah use were strongly genetically correlated (rg=0.87). Cross-trait correlations diverged: cigarette, e-nicotine, and smokeless tobacco use showed the strongest positive correlations with psychiatric disorders, negative urgency, and neuroticism, whereas cigar and hookah use showed null-to-weak correlations with psychiatric disorders but positive correlations with sensation-seeking and openness. Conclusions Our findings reveal important phenotypic and genetic distinctions across modes of nicotine use, particularly in relation to personality traits such as impulsivity and to socioeconomic context.