1. ¹Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2. ²Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Upper Merion, PA, USA
3. ³Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Verona, Italy
4. ⁴Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA
5. ⁵University of Toronto, Toronto, ON, Canada

Correspondence: Professor W Berrettini, Department of Psychiatry, University of Pennsylvania School of Medicine, room 2206 125 S. 31st Street, Philadelphia, PA 19104, USA. E-mail: wadeb@mail.med.upenn.edu

Received 14 December 2007; Accepted 17 December 2007; Published online 29 January 2008.

Abstract

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.