rs1051730 (CHRNA3): Smoking quantity and lung risk

Key takeaways

• rs1051730 is one of the strongest known genetic predictors of cigarettes smoked per day, with each copy of the A allele linked to roughly one additional cigarette daily.
• The variant sits within the 15q25.1 nicotinic receptor gene cluster (CHRNA3/CHRNA5/CHRNB4), which encodes proteins that bind nicotine in the brain, muscle, nerve, and heart.
• In smokers, this locus is also linked to measurably reduced lung function and higher risk of peripheral artery disease.
• The 15q25.1 region is a leading genome-wide association locus for lung cancer, with pathway evidence pointing to nicotinic receptor signaling as a mechanism.
• GTEx expression data show this variant is associated with reduced expression of both CHRNA3 and CHRNA5 across brain, skeletal muscle, and other tissues.

What the research says

rs1051730 is a synonymous variant (a DNA change that does not alter the resulting protein sequence) in CHRNA3, which encodes the alpha-3 subunit of the neuronal nicotinic acetylcholine receptor, a protein that binds nicotine and the neurotransmitter acetylcholine throughout the brain and body. In a meta-analysis of up to 143,023 individuals, each copy of the A allele was associated with approximately 1 additional cigarette per day (beta = 1.03, SE = 0.056, P = 2.8 x 10^-73), accounting for 0.5% of variance in smoking quantity PMID 20418889. The broader 15q25.1 gene cluster explains roughly 1% of phenotypic variance in smoking quantity and approximately 4-5% of variance in cotinine, a biological marker of nicotine intake PMID 31861374.

Reported associations

• Cigarettes per day: Each copy of the A allele at rs1051730 is associated with approximately 1 additional cigarette per day (beta = 1.03, SE = 0.056, P = 2.8 x 10^-73, n up to 143,023) PMID 20418889.
• Cigarettes per day (independent meta-analysis): In 41,150 individuals, each A allele copy was associated with 0.079 additional cigarettes per day (95% CI 0.070-0.088, P = 9.45 x 10^-19) PMID 20418890.
• Peripheral artery disease (primary analysis): The CHRNA3 locus was identified as one of five genome-wide significant loci for peripheral artery disease (PAD, a condition of reduced blood flow in the limbs) in a primary meta-analysis of 449,548 individuals including 12,086 PAD cases, overlapping previously reported associations.
• Peripheral artery disease in smokers (interaction effect): A nearby variant at this locus (rs12910984) was specifically associated with PAD in ever-smokers (OR 1.15, 95% CI 1.11-1.19, P = 9.3 x 10^-10), with a statistically significant smoking-by-genotype interaction (P_interaction = 3.9 x 10^-5), indicating that the genotype effect is modified by smoking status.
• Lung cancer susceptibility: The 15q25.1 locus is a leading GWAS-identified susceptibility region for lung cancer; pathway analysis in 42,901 individuals identified the neuroactive ligand-receptor interaction pathway and gated channel activity as likely mediating mechanisms PMID 30333490.
• Pulmonary function in smokers: This cluster was significantly associated with both FEV1 (the volume of air exhaled in one second, a standard airflow measure) and the FEV1/FVC ratio (a measure of airflow obstruction) in 9,919 current and former smokers (lowest P = 2.17 x 10^-11 among non-Hispanic whites), confirmed in a meta-analysis totalling 13,532 participants PMID 26754954.
• Heavy smoking in Hispanic/Latino populations: A nearby functional variant in CHRNA5 (rs16969968, which changes the amino acid sequence of the alpha-5 receptor subunit) was associated with heavy smoking (more than 10 cigarettes per day) in Hispanic/Latino ever-smokers (OR 1.32 for the minor A allele, P = 2.20 x 10^-7; n = 1,929 ever-smokers), with minor allele frequencies ranging from 0.17 to 0.29 across ancestry subgroups.

Evidence quality

The association of rs1051730 with cigarettes per day is among the best-replicated findings in behavioral genetics. The Tobacco and Genetics Consortium meta-analysis in up to 143,023 individuals (P = 2.8 x 10^-73) PMID 20418889 and an independent meta-analysis in 41,150 individuals (P = 9.45 x 10^-19) PMID 20418890 both far exceed the standard genome-wide significance threshold of P < 5 x 10^-8, with consistent effect size estimates across diverse cohorts. Even within the initial discovery cohort alone (n = 38,181 for cigarettes per day), the minimum P-value across the 15q25.1 region reached 4.2 x 10^-35 PMID 20418889. Associations with lung cancer (replicated in 42,901 individuals) PMID 30333490 and pulmonary function in smokers (meta-analysis n = 13,532) PMID 26754954 are each supported by multiple independent cohorts. The PAD association was confirmed in a meta-analysis of 449,548 individuals but is context-specific: the smoking-stratified signal shows a statistically significant interaction with smoking status, suggesting that genetic and environmental factors act together rather than independently. A key source of ongoing uncertainty involves causal variant identification: fine-mapping with 1000 Genomes data identified a promoter SNP in CHRNA5 (rs55853698) as showing marginally higher statistical significance than rs1051730 after imputation, and a secondary independent signal at rs6495308 within a CHRNA3 intron was also detected PMID 20418890. A separate conditional analysis identified residual signals at CHRNA5 and nearby loci after adjusting for rs1051730 PMID 20418889, indicating that at least two partially independent loci within the cluster contribute to the observed associations. Overall, known genome-wide significant loci explain only about 2% of the estimated genetic heritability of smoking behavior, which is estimated at 40-60% PMID 31861374, meaning rs1051730, while highly significant, captures only a fraction of the total genetic contribution to smoking quantity.

Tissue-specific expression effects

• CHRNA5: This variant is associated with reduced expression of CHRNA5 (encoding the alpha-5 nicotinic acetylcholine receptor subunit) in multiple tissues, including brain regions (anterior cingulate cortex, cerebral cortex, frontal cortex), skeletal muscle, tibial nerve, heart (atrial appendage), and cultured fibroblasts GTEx Portal.
• CHRNA3: This variant is associated with reduced expression of CHRNA3 (encoding the alpha-3 nicotinic acetylcholine receptor subunit) in skeletal muscle GTEx Portal.

Lifestyle considerations

No lifestyle considerations on file for this variant.