Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking

Sarah H. Stephens, Sarah M. Hartz, Nicole R. Hoft, Nancy L. Saccone, Robin C. Corley, John K. Hewitt, Christian J. Hopfer, Naomi Breslau, Hilary Coon, Xiangning Chen, Francesca Ducci, Nicole Dueker, Nora Franceschini, Josef Frank, Younghun Han, Nadia Hansel, Chenhui Jiang, Tellervo Korhonen, Penelope A. Lind, Jason LiuLeo Pekka Lyytikäinen, Martha Michel, John R. Shaffer, Susan E. Short, Juzhong Sun, Alexander Teumer, John R. Thompson, Nicole Vogelzangs, Jacqueline M. Vink, Angela Wenzlaff, William Wheeler, Bao Zhu Yang, Steven H. Aggen, Anthony J. Balmforth, Sebastian E. Baumeister, Terri L Beaty, Daniel J. Benjamin, Andrew W. Bergen, Ulla Broms, David Cesarini, Nilanjan Chatterjee, Jingchun Chen, Yu Ching Cheng, Sven Cichon, David Couper, Francesco Cucca, Danielle Dick, Tatiana Foroud, Helena Furberg, Ina Giegling, Nathan A. Gillespie, Fangyi Gu, Alistair S. Hall, Jenni Hällfors, Shizhong Han, Annette M. Hartmann, Kauko Heikkilä, Ian B. Hickie, Jouke Jan Hottenga, Pekka Jousilahti, Marika Kaakinen, Mika Kähönen, Philipp D. Koellinger, Stephen Kittner, Bettina Konte, Maria Teresa Landi, Tiina Laatikainen, Mark Leppert, Steven M. Levy, Rasika Mathias, Daniel W. Mcneil, Sarah E. Medland, Grant W. Montgomery, Tanda Murray, Matthias Nauck, Kari E. North, Peter D. Paré, Michele Pergadia, Ingo Ruczinski, Veikko Salomaa, Jorma Viikari, Gonneke Willemsen, Kathleen C. Barnes, Eric Boerwinkle, Dorret I. Boomsma, Neil Caporaso, Howard J. Edenberg, Clyde Francks, Joel Gelernter, Hans Jörgen Grabe, Hyman Hops, Marjo Riitta Jarvelin, Magnus Johannesson, Kenneth S. Kendler, Terho Lehtimäki, Patrik K E Magnusson, Mary L. Marazita, Jonathan Marchini, Braxton D. Mitchell, Markus M. Nöthen, Brenda W. Penninx, Olli Raitakari, Marcella Rietschel, Dan Rujescu, Nilesh J. Samani, Ann G. Schwartz, Sanjay Shete, Margaret Spitz, Gary E. Swan, Henry Völzke, Juha Veijola, Qingyi Wei, Chris Amos, Dale S. Cannon, Richard Grucza, Dorothy Hatsukami, Andrew Heath, Eric O. Johnson, Jaakko Kaprio, Pamela Madden, Nicholas G. Martin, Victoria L. Stevens, Robert B. Weiss, Peter Kraft, Laura J. Bierut, Marissa A. Ehringer

Research output: Contribution to journalArticle

Abstract

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

Original languageEnglish (US)
Pages (from-to)846-859
Number of pages14
JournalGenetic Epidemiology
Volume37
Issue number8
DOIs
StatePublished - Dec 2013

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Keywords

  • CHRNA3
  • CHRNA5
  • CHRNB4
  • Meta-analysis
  • Nicotine
  • Smoke

ASJC Scopus subject areas

  • Genetics(clinical)
  • Epidemiology

Cite this

Stephens, S. H., Hartz, S. M., Hoft, N. R., Saccone, N. L., Corley, R. C., Hewitt, J. K., Hopfer, C. J., Breslau, N., Coon, H., Chen, X., Ducci, F., Dueker, N., Franceschini, N., Frank, J., Han, Y., Hansel, N., Jiang, C., Korhonen, T., Lind, P. A., ... Ehringer, M. A. (2013). Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genetic Epidemiology, 37(8), 846-859. https://doi.org/10.1002/gepi.21760