Phenotypic and genetic characterization of different modes of lifetime nicotine use in the All of Us Research Program
Huang, F., Romero Villela, P. N., Luo, Z., Miller, A. P., Madden, P., Agrawal, A., Hatoum, A. S., Johnson, E. C.
genetic and genomic medicine
Quick verdict
N=304k AoU GWAS claims two nicotine-use genetic clusters; a contradictory Δχ² report and mismatched case definitions leave that headline shaky.
Summary
This preprint reports the first biobank-scale genome-wide association study (GWAS) of five modes of lifetime nicotine use — electronic nicotine products, cigars, hookah, smokeless tobacco, and ≥100 lifetime cigarettes — in 304,213 All of Us participants, analyzed separately in European, Admixed American, and African ancestry groups and combined via MR-MEGA cross-ancestry meta-analysis. The meta-analysis identified 87 genome-wide significant loci for cigarette use, 4 for e-nicotine, 1 each for cigar and smokeless tobacco use, and none for hookah; MAGMA gene-based tests implicate THSD7B and NCAM1 across modes. Within European ancestry, LD score regression and GenomicSEM support two genetic clusters: cigarette, e-nicotine, and smokeless tobacco use load on a factor correlated with psychiatric disorders, negative urgency, and neuroticism, while cigar and hookah use form a second factor tied to sensation-seeking and openness, with hookah uniquely positively correlated with educational attainment. Limitations include a threshold asymmetry (≥100 cigarettes versus ever use for other modes) that may confound the cluster interpretation, very large standard errors for cross-ancestry correlations of hookah and smokeless use, genetic correlations with external traits restricted to European ancestry, and an internally contradictory constrained-factor χ² test (Δχ²=-0.0001, p=1) reported as a significant degradation.
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Assessment at a glance
6
risk flags identified
● high 1
● medium 2
● low 3
5 strengths · 5 weaknesses · 5 author questions
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Key claims under review
- Cross-ancestry GWAS meta-analysis identifies 87 genome-wide loci for ≥100-cigarette use, 4 for e-nicotine, 1 for cigar, 1 for smokeless tobacco, and none for hookah use.
- GenomicSEM partitions the five nicotine-use modes into two genetic clusters: cigarette/e-nicotine/smokeless (dependence-like) versus cigar/hookah (social-use), with a factor correlation of 0.64.
- The dependence-like cluster is genetically correlated with psychiatric disorders, negative urgency and neuroticism, while the cigar-hookah cluster correlates with sensation-seeking and openness and shows a unique positive hookah–educational-attainment correlation.
- All modes are positively associated with tobacco use disorder diagnoses in single-variable models, but hookah and cigar associations become inverse after mutual adjustment.
Strengths
First biobank-scale GWAS of non-cigarette nicotine modes
Moves beyond the cigarette-centric literature by phenotyping e-nicotine, cigar, hookah and smokeless ever-use (Table 1) with ancestry-stratified GWAS in EUR (181,797), AFR (64,306) and AMR (58,110) plus cross-ancestry meta-analysis (Neff 12,579–174,840).
Ancestry-aware analysis with honest power reporting
PLINK2 GWAS with within-ancestry PCs, POPCORN rge/rgi, LDSC gated on the z>4 power rule (AFR excluded from genetic correlations), and explicit flagging of POPCORN SEs ≥1.00 for hookah and smokeless use.
Formal multivariate genetic modeling
Phenotype–genetics triangulation
Candid limitations
Weaknesses
Internally contradictory GenomicSEM constrained-model test
Case-definition asymmetry confounds the headline clusters
Ancestry heterogeneity unmodeled and unreported
External genetic correlations are EUR-only
No code or summary-statistics availability in the manuscript text
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Scope & Claims
This preprint (medRxiv, posted 2026-09-17, not peer reviewed) claims the first biobank-scale phenotypic and genetic characterization of five lifetime nicotine-use modes in the All of Us (AoU) Research Program: ever use of e-nicotine products, cigars, hookah tobacco and smokeless tobacco, plus ≥100 lifetime cigarettes. The central claim is that nicotine use is not a homogeneous phenotype: cross-ancestry GWAS in N=304,213 identifies 87 genome-wide loci for cigarette use, 4 for e-nicotine, 1 each for cigar and smokeless tobacco, none for hookah; and GenomicSEM partitions the traits into two clusters — a dependence-like cluster (cigarette, e-nicotine, smokeless) correlated with psychiatric disorders, negative urgency and neuroticism, and a social-use cluster (cigar, hookah) correlated with sensation-seeking and openness, with hookah uniquely positively correlated with educational attainment (rg=0.28, SE=0.044). The framing is clear and the data appropriate; the question is whether the statistics carry the weight.
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- Methods & statistical evidence assessment
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Frequently asked questions
Did this study find genes for vaping and other non-cigarette nicotine use?
Yes, but few. In 304,213 All of Us participants, the cross-ancestry GWAS found 4 genome-wide significant loci for e-nicotine (vaping) ever use, 1 for cigar use, and 1 for smokeless tobacco use, none for hookah use — versus 87 loci for having smoked at least 100 cigarettes.
Is genetic risk for hookah and cigar use the same as for cigarettes?
The paper argues yes: hookah and cigar use are strongly genetically correlated with each other (rg=0.87) and form one cluster linked to sensation-seeking and openness, while cigarette, e-nicotine and smokeless tobacco use form a second cluster linked to psychiatric disorders, negative urgency and neuroticism. The two clusters still correlate ~0.64, so the risks overlap substantially — and the strongest statistical test for this split is internally contradictory in the current preprint.
Does this study show nicotine use causes mental illness?
No. It reports genetic correlations, meaning shared genetic influences between nicotine-use traits and psychiatric traits. Genetic correlation does not establish causation, and the authors note that population-based GWAS may reflect gene-environment correlation and assortative mating rather than direct genetic effects.
How big was the study and whose data were used?
304,213 adults with whole-genome sequencing from the NIH All of Us Research Program (controlled-tier v8), split into European ancestry (181,797), Admixed American (58,110) and African (64,306) groups, with nicotine-use modes measured by self-report in the Lifestyle survey.
About this review
This is an AI-generated preliminary review by Evolve.Pub, produced from the openly available text of the paper. It is not peer review and does not represent the authors' views. The canonical record of the paper is at the publisher link above.
- Figures 1–4 are image-only (UpSet plots, heatmaps, SEM diagrams); overlaps and loadings could not be verified visually
- Supplementary Tables ST1–ST9 (heritabilities, full locus/gene lists, trait list) were not in the extracted text
- No data/code availability section appears in the extracted text; codeAvailable=false reflects absence of any statement, not a confirmed negative
- Minor OCR artifacts (e.g., truncated exponent in p < 5 × 10⁻), but all cited statistics appear in prose and were checked against each other
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