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We conducted a 1000 Genomes–imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit ( CHRNA4)  gene on chromosome 20q13: lowest  P =8.0 × 10 −9  across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08–1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate  CHRNA4  transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased  CHRNA4  expression in physiologically normal human brains (lowest  P =7.3 × 10 −4 ). Importantly, rs2273500-C was associated with increased lung cancer risk ( N =28 998, odds ratio=1.06 and 95% confidence interval=1.00–1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single ‘cigarettes per day' item, we identified a common  CHRNA4  variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence