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Association of nicotinic acetylcholine receptor subunit α4 polymorphisms with nicotine dependence in 5500 Germans

The Pharmacogenomics Journal volume 9, pages 219–224 (2009)Cite this article

Abstract

Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit α4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N1=1412; N2=1855; N3=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (⩽100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case–control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N=1030). The most significant association was observed between rs2236196 and FTND (P=0.0023), whereas the closely linked rs1044396 had most statistical support in the case–control models (P=0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3′-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence.

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Acknowledgements

We thank the study participants and personnel contributing to all aspects of the studies involved. The present work was funded by grants within the German Research Foundation (DFG) national priority program SPP1226 ‘Nicotine: Physiological and Molecular Effect in the CNS’ (Br1704/11-1, Da370/5-1, Ga804/1-1, Ru744/4-1, Wi1316/6-1, Wi1316/7-1). KORA was supported by the German Federal Ministry of Education and Research (BMBF), the State of Bavaria and the National Genome Research Network (NGFN). NCOOP was supported in parts by the University of Mainz, BMBF (no. 01EB0113), DFG (Wi2997/1-1) and further BMBF funding is gratefully acknowledged (Project Berlin Neuroimaging Center, no. 01G00208). ESTHER was supported by the Baden Württemberg Ministry of Research, Science and Arts. Genotyping was carried out at the Genome Analysis Center (GAC) of the Helmholtz Zentrum München (KORA, ESTHER) and the Genetics Research Centre, which is an initiative by GlaxoSmithKline and LMU, Munich/Germany (NCOOP). The funding sources played a role neither in study design and conduct nor in the analysis, interpretation or publication of the data and results.

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Authors and Affiliations

  1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

    L P Breitling, H Müller, E Raum, D Rothenbacher & H Brenner

  2. Department of Psychiatry, University of Mainz, Mainz, Germany

    N Dahmen & C Fehr

  3. Institute of Epidemiology, Helmholtz Zentrum München,, Neuherberg, Germany

    K Mittelstraß, C Lamina, T Illig & H-E Wichmann

  4. Department of Psychiatry, Ludwig Maximilians University, Munich, Germany

    D Rujescu & I Giegling

  5. Department of Psychiatry, Charité University Medicine Berlin, Campus Mitte, Berlin, Germany

    J Gallinat

  6. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbrnuck, Austria

    C Lamina

  7. Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany

    T Illig

  8. Department of Psychiatry, Heinrich Heine University, Düsseldorf, Germany

    G Winterer

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  1. L P Breitling
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Correspondence to L P Breitling.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Breitling, L., Dahmen, N., Mittelstraß, K. et al. Association of nicotinic acetylcholine receptor subunit α4 polymorphisms with nicotine dependence in 5500 Germans. Pharmacogenomics J 9, 219–224 (2009). https://doi.org/10.1038/tpj.2009.6

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