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Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these ∼7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P = 6.9 × 10−5). In a third set of European populations (n = ∼7500) which had been genotyped for ∼6000 SNPs in ∼2000 genes, an allele in the same haplotype was associated with CPD (nominal P = 2.6 × 10−6). These results (in three independent populations of European origin, totaling ∼15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.