What you carry at this position in your DNA and what research says about it.
Nicotine Dependence Risk: 9/10 evidence, 72 publications.
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Sample genotype (not yours): G/G
Typical Risk of Nicotine Dependence and Lung Diseases
Presence of the common G allele on both chromosomes is associated with a typical risk of nicotine addiction and smoking-related illnesses. Natural, slightly unpleasant initial sensations of smoking generally occur with this profile, acting as a deterrent.
What this genotype means: Typical risk of nicotine dependence; Lower likelihood of heavy smoking; Typical baseline risk for lung cancer and COPD.
Sample genotype (not yours): A/A
Increased Risk of Nicotine Dependence and Lung Diseases
Two copies of the A allele are associated with a significantly higher risk of nicotine addiction and heavier smoking. Serious smoking-related conditions, including lung cancer and COPD, also show elevated risks with this profile.
What this genotype means: Higher risk of severe nicotine dependence; Increased risk of lung cancer and COPD; Better response to smoking cessation medications.
Sample genotype (not yours): G/A
Slightly Increased Risk of Nicotine Dependence
A single copy of the A allele is linked to a slightly higher risk of nicotine addiction and heavier daily smoking. Elevated risks for smoking-related lung conditions like COPD and lung cancer are also associated with this profile.
What this genotype means: Slightly higher risk of nicotine addiction; Slightly increased risk of lung cancer and COPD; Potentially better response to varenicline for quitting.
Gene function and biological role
Gene Function: The CHRNA5 gene encodes the alpha 5 subunit of the nicotinic acetylcholine receptor, which forms ion channels activated by acetylcholine and nicotine. These receptors are highly expressed in brain regions involved in reward pathways, such as the ventral tegmental area, and in peripheral tissues like the lungs [1]. Alterations in this subunit can significantly change how the brain responds to nicotine exposure [2]. Studies suggest that genetic variation in this gene influences the density and functional properties of these receptors [3]. This receptor family plays a central role in mediating both the rewarding and aversive effects of tobacco smoke [4].
Variant Impact: A single nucleotide substitution in the CHRNA5 gene causes an amino acid change from aspartate to asparagine at position 398. The structural change reduces the calcium ion flow through the nicotinic receptor channel upon activation [5]. This functional impairment dampens the brain's natural protective, aversive response to high doses of nicotine [4]. Consequently, individuals carrying the variant allele may require more nicotine to achieve the same physiological effect, reinforcing smoking behavior [6]. The variant is also strongly linked to structural and functional changes in brain circuits that support addiction [7].
Read on the Nicotine Receptor page
Key Insight: The same genetic variant that increases the risk of nicotine addiction actually reduces the risk of cocaine dependence.
Location: CHRNA5. Chromosome 15 · 15q25.1 · 78.6 Mb
Estimated prevalence by population
Global 59.4%; European 42.6%; African 88.5%; East Asian 93.7%; South Asian 60.6%; Americas 59.9%; Ashkenazi 39.0%; Finnish 45.3%; Middle Eastern 35.8%; Amish 35.2%.
Estimated GG genotype frequency.
Global 33.1%; European 45.3%; African 11.1%; East Asian 6.2%; South Asian 34.5%; Americas 35.0%; Ashkenazi 46.9%; Finnish 44.0%; Middle Eastern 48.1%; Amish 48.3%.
Estimated GA genotype frequency.
Global 7.5%; European 12.0%; African 0.4%; East Asian 0.1%; South Asian 4.9%; Americas 5.1%; Ashkenazi 14.1%; Finnish 10.7%; Middle Eastern 16.1%; Amish 16.6%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Neurology & Mental Health
Addiction & Reward
Nicotine Dependence. Evidence: 9/10. Source: PMID 31294817. Typical Risk.
Cigarettes Per Day. Evidence: 10/10. Source: PMID 29758381. Typical.
Cocaine Addiction Risk. Evidence: 3/10. Source: PMID 32841724. Typical Risk.
Cancer & Oncology
Lung Cancer
Lung Cancer. Evidence: 10/10. Source: PMID 37167549. Typical Risk.
Organ Systems
Respiratory Health
COPD. Evidence: 8/10. Source: PMID 33909500. Typical Risk.
Showing effects for A/A genotype
Nicotine Dependence. Evidence: 9/10. Source: PMID 31294817. ~1.9x Increased Risk.
Cigarettes Per Day. Evidence: 10/10. Source: PMID 29758381. Higher.
Cocaine Addiction Risk. Evidence: 3/10. Source: PMID 32841724. ~33% Lower Risk.
Lung Cancer. Evidence: 10/10. Source: PMID 37167549. Increased Risk.
COPD. Evidence: 8/10. Source: PMID 33909500. Increased Risk.
Showing effects for G/A genotype
Nicotine Dependence. Evidence: 9/10. Source: PMID 31294817. Slightly Increased.
Cigarettes Per Day. Evidence: 10/10. Source: PMID 29758381. Slightly Higher.
Cocaine Addiction Risk. Evidence: 3/10. Source: PMID 32841724. Slightly Lower Risk.
Lung Cancer. Evidence: 10/10. Source: PMID 37167549. Slightly Increased.
COPD. Evidence: 8/10. Source: PMID 33909500. Slightly Increased.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Baseline genetic receptor activity is maintained with this common profile. Because the receptors function with normal sensitivity, nicotine exposure triggers typical signaling pathways, including the natural aversive responses to high doses [1]. Consequently, severe nicotine dependence is less likely to develop compared to profiles carrying the A variant [2]. Average daily cigarette consumption also remains lower if smoking occurs [3]. This lower exposure directly translates to a typical, un-elevated risk for chronic obstructive pulmonary disease (COPD) and lung cancer [4]. However, the protective effect against cocaine dependence seen with the variant allele is absent here [5]. Standard smoking cessation aids work effectively if needed [6].
Typical risk of nicotine dependence; Lower likelihood of heavy smoking; Typical baseline risk for lung cancer and COPD.
Sample genotype: AA (Homozygous)
Nicotinic receptors in the brain have significantly reduced functional response to nicotine when this profile is present [1]. This blunted sensitivity reduces the natural, unpleasant side effects of early smoking, making the transition to heavy use much easier [2]. Daily cigarette consumption is typically higher, and the time to the first cigarette of the day is shorter [3]. The resulting high exposure to tobacco smoke substantially increases the risk of lung cancer and chronic obstructive pulmonary disease [4]. On the positive side, a significantly lower risk of cocaine dependence is linked to this profile [5]. For those trying to quit, clinical studies show better success rates when using smoking cessation therapies like varenicline or bupropion [6].
Higher risk of severe nicotine dependence; Increased risk of lung cancer and COPD; Better response to smoking cessation medications.
Sample genotype: GA (Heterozygous)
Inheriting one copy of the variant A allele alters a portion of the brain's nicotinic receptors, reducing their sensitivity to nicotine [1]. This blunted response can make the first experiences with smoking feel more pleasurable and less harsh, increasing the likelihood of developing a habit [2]. Over time, daily cigarette consumption tends to be slightly higher to satisfy cravings [3]. This increased tobacco exposure contributes to an elevated risk of chronic obstructive pulmonary disease and lung cancer [4]. Interestingly, a slightly lower risk of developing cocaine dependence is also associated with this profile [5]. When attempting to quit smoking, cessation medications like varenicline or bupropion may show a more favorable response [6].
Slightly higher risk of nicotine addiction; Slightly increased risk of lung cancer and COPD; Potentially better response to varenicline for quitting.
Variants with shared genetic architecture
rs17486278 · CHRNA5 Gene · Chr 15 · Lung Disease Risk
rs55781567 · CHRNA5 Gene · Chr 15 · Lung Cancer Risk
rs2036527 · CHRNA5 Gene · Chr 15 · Smoking and Lung Cancer Risk
Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele.
In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression.
A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.
Crucial role of nicotinic α5 subunit variants for Ca2+ fluxes in ventral midbrain neurons.
A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.
Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.
A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.
Function of human α3β4α5 nicotinic acetylcholine receptors is reduced by the α5(D398N) variant.
Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.
A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.
Content updated August 2026.
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