Hancock, D BReginsson, G WGaddis, N CChen, XSaccone, N LLutz, S MQaiser, BSherva, RSteinberg, SZink, FStacey, S NGlasheen, CChen, JGu, FFrederiksen, B NLoukola, AGudbjartsson, D FBrüske, ILandi, M TBickeböller, HMadden, PFarrer, LKaprio, JKranzler, H RGelernter, JBaker, T BKraft, PAmos, C ICaporaso, N EHokanson, J EBierut, L JThorgeirsson, T EJohnson, E OStefansson, K2016-08-092015Hancock, D. B., G. W. Reginsson, N. C. Gaddis, X. Chen, N. L. Saccone, S. M. Lutz, B. Qaiser, et al. 2015. “Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.” Translational Psychiatry 5 (10): e651. doi:10.1038/tp.2015.149. http://dx.doi.org/10.1038/tp.2015.149.2158-3188http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822338We 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.en-USJournal Article2016-08-0910.1038/tp.2015.149