In our study, we categorized nicotine dependence as mild (FTND score 0–3 or low-level smoking), moderate (FTND score 4–6) or severe (FTND score 7–10) among study participants, all of European-ancestry, who reported smoking more than 100 cigarettes in their lifetime. We conducted a 1000 Genomes–imputed GWAS meta-analysis of nicotine dependence across five study samples (total N=17 074), identified the alpha-4 nicotinic receptor subunit (CHRNA4) gene as a novel genome-wide significant locus, tested top CHRNA4 variants for replication in five independent study samples (total N=7469) and conducted follow-up association testing with lung cancer using six study samples (total N=12 160 cases and 16 838 controls). Our results revealed that rs2273500, a splice site acceptor SNP with important regulatory effects for CHRNA4, was associated with risk of developing both nicotine dependence and lung cancer.
