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α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking

Molecular Psychiatry volume 13, pages 368–373 (2008)Cite this article

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.

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Acknowledgements

We thank Sreekumar Pillai, for helpful discussions. Allen Roses, Lefkos Midleton, Perry Nisen, Paul Matthews and Emilangelo Ratti are thanked for their support of these genetic studies. We are indebted to the GEMS/Lausanne investigators, including Antero Kesaniemi, Gerard Waeber, Phil Barter, Bob Mahley, Ruth McPherson, Scott Grundy and Tom Bersot. Supplementary information is available at the Molecular Psychiatry website. WHB was supported by NIDA Grant P60 05186 to Charles O'Brien, MD, PhD, by a grant from the Tzedekah Foundation, by the Veterans Administration VISN4 Mental Illness Research, Education and Clinical Center (David Oslin, MD, PI, USA) and by a grant from Philip and Marcia Cohen.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    W Berrettini

  2. Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Upper Merion, PA, USA

    W Berrettini, X Yuan, F Tozzi, K Song, C Francks, D Waterworth, P Muglia & V Mooser

  3. Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Verona, Italy

    W Berrettini, X Yuan, F Tozzi, K Song, C Francks, D Waterworth, P Muglia & V Mooser

  4. Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA

    H Chilcoat

  5. University of Toronto, Toronto, ON, Canada

    P Muglia

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  1. W Berrettini
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Correspondence to W Berrettini.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Berrettini, W., Yuan, X., Tozzi, F. et al. α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13, 368–373 (2008). https://doi.org/10.1038/sj.mp.4002154

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