What this means

CHRNA5 codes for the α5 subunit of the neuronal nicotinic acetylcholine receptor, the brain's main nicotine target. The rs16969968 G>A variant changes amino acid 398 (Asp→Asn) and alters receptor function. Among smokers, A-allele carriers smoke more cigarettes per day, achieve higher nicotine intake per cigarette, are more likely to be nicotine- dependent, find it harder to quit, and — partly as a consequence — have meaningfully elevated lung-cancer risk. It is one of the cleanest and most-replicated common-variant findings in behavioural genetics. The catch (and it matters): the lung-cancer signal is essentially *conditional on smoking*. People with two A alleles who never smoke carry no measurable lung-cancer risk from this variant.

CHRNA5 makes part of the brain's main nicotine receptor. A common DNA change in this gene tweaks how that receptor works. The effect only shows up in smokers: people who smoke and carry the change get more out of each cigarette in nicotine terms, end up smoking more per day, find it harder to quit, and have a higher risk of lung cancer than smokers without the change. The crucial point is that this is all *conditional on smoking*. If you don't smoke, this variant doesn't affect you. It is, in a way, one of the strongest pieces of evidence for "don't start" we have from common-variant genetics.

Caveats

• The lung-cancer signal is conditional on smoking — non-smokers carry no measurable risk from this variant.
• The effect on cigarettes per day is meaningful (≈1 extra/day per A allele in heavy smokers) but small at the individual level.
• Pharmacotherapy for smoking cessation (varenicline, NRT) appears to work as well or better in A-allele carriers.
• Most studied in European-ancestry cohorts; effect sizes broadly replicate across populations.

Populations

• Studied across European, East Asian, and African ancestries; allele frequencies vary

References

• Thorgeirsson et al. — A variant associated with nicotine dependence, lung cancer and peripheral arterial disease (Nature, 2008)
• Hung et al. — A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 (Nature, 2008)
• Liu et al. — Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use (Nature Genetics, 2019)