GWAS analyses of nicotine dependence phenotypes14–24 have firmly established associations with several loci, including nicotinic acetylcholine receptor genes on chromosomes 15q25 (CHRNA5-CHRNA3-CHRNB4), 8p11 (CHRNB3-CHRNA6), and 20q13 (CHRNA4). The largest GWAS meta-analyses relied on widely ascertained phenotypes such as cigarettes per day (CPD),16–18 which represents only one of several components of nicotine dependence.25 Focusing GWAS on nicotine dependence rather than CPD may improve statistical power for identifying variants that influence the broader construct of dependence.19 This idea is supported by our prior nicotine dependence GWAS meta-analysis (total N=17,074 ever-smokers of European/European American ancestry [EUR]) that discovered associations with CHRNA4 SNPs that were driven by time to first cigarette in the morning (TTFC) and had not been detected in GWAS meta-analyses of CPD with much larger sample sizes.23 To improve statistical power further and to search for additional loci, we more than doubled our sample size to perform the largest GWAS meta-analysis of nicotine dependence to date, including 38,602 ever-smokers (28,677 of EUR and 9,925 of African American [AA] ancestries) across 15 studies. We extended our study to include correlations with DNA
