Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program
- 1Washington University School of Medicine
Abstract
ObjectiveExisting genetic studies of nicotine consumption have largely focused on cigarette smoking, despite other modes emerging. Different nicotine use modes have varying use patterns and user characteristics that may contribute to distinct environmental and genetic influences. This study aims to identify the shared and specific genetic risks for five nicotine use modes.
MethodsWe 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.
ResultsNicotine 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.
ConclusionsOur 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.
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BibTeX
@misc{huang2026phenotypic,
title = {{Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program}},
author = {F. Huang and P. N. Romero Villela and Z. Luo and A. P. Miller and P. Madden and A. Agrawal and A. S. Hatoum and E. C. Johnson},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.26361370},
url = {https://www.medrxiv.org/content/10.64898/2026.09.11.26361370v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program
AU - F. Huang
AU - P. N. Romero Villela
AU - Z. Luo
AU - A. P. Miller
AU - P. Madden
AU - A. Agrawal
AU - A. S. Hatoum
AU - E. C. Johnson
PY - 2026
DA - 2026/09/11
PB - medRxiv
DO - 10.64898/2026.09.11.26361370
UR - https://www.medrxiv.org/content/10.64898/2026.09.11.26361370v1
AB - ObjectiveExisting genetic studies of nicotine consumption have largely focused on cigarette smoking, despite other modes emerging. Different nicotine use modes have varying use patterns and user characteristics that may contribute to distinct environmental and genetic influences. This study aims to identify the shared and specific genetic risks for five nicotine use modes. MethodsWe 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. ResultsNicotine 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. ConclusionsOur 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.
ER -