Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers

Arch Gen Psychiatry. 2012 Aug;69(8):854-60. doi: 10.1001/archgenpsychiatry.2012.124.


Context: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.

Objective: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.

Data sources: Primary data.

Study selection: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.

Data extraction: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.

Data synthesis: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01).

Conclusion: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adolescent Development / drug effects
  • Adult
  • Age of Onset
  • Europe / epidemiology
  • Female
  • Gene-Environment Interaction
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Nerve Tissue Proteins / genetics*
  • Nicotine / pharmacology
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic / genetics*
  • Severity of Illness Index
  • Smoking* / epidemiology
  • Smoking* / genetics
  • Tobacco Use Disorder* / epidemiology
  • Tobacco Use Disorder* / genetics
  • Tobacco Use Disorder* / psychology


  • CHRNA5 protein, human
  • Nerve Tissue Proteins
  • Receptors, Nicotinic
  • Nicotine

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