Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking
Year: 2013
Type: article
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.
DOI: 10.17615/y70w-zg61
Authors: Sarah H. Stephens, Sarah M. Hartz, Nicole R. Hoft, Nancy L. Saccone, Robin Corley, John K. Hewitt, Christian J. Hopfer, Naomi Breslau, Hilary Coon, Xiangning Chen, Francesca Ducci, Nicole Dueker, Nora Franceschini, Josef Frank, Younghun Han, Nadia N. Hansel, Chenhui Jiang, Tellervo Korhonen, Penelope A. Lind, Jason Liu, Leo-Pekka Lyytikaeinen, Martha Tarasco Michel, John R. Shaffer, Susan E. Short, Juzhong Sun, Alexander Teumer, J. Thompson, Nicole Vogelzangs, Jacqueline M. Vink, Angela S. Wenzlaff, William Wheeler, Bao‐Zhu Yang, Steven H. Aggen, Anthony J. Balmforth, Sebastian E. Baumeister, Terri H. 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 M. Dick, Tatiana Foroud, Helena Furberg, Ina Giegling, Nathan A. Gillespie, Fangyi Gu, Alistair S. Hall, Jenni Haellfors, Shizhong Han, Annette M. Hartmann, Kauko Heikkilae, Ian B. Hickie, Jouke‐Jan Hottenga, Jari Lahti, Marika Kaakinen, Mika Kaehoenen, Philipp Koellinger, S. J. Kittner, Bettina Konte, Maria‐Teresa Landi, Tiina Laatikainen, Mark Leppert, Steven M. Levy, Rasika A. Mathias, Daniel W. McNeil, Sarah E. Medland, Grant W. Montgomery, Tanda Murray, Matthias Nauck, Kari E. North, Peter D. Paré, Michele L. Pergadia, Ingo Ruczinski, Veikko Salomaa, Jorma Viikari, Gonneke Willemsen, Kathleen C. Barnes, Eric Boerwinkle, Dorret I. Boomsma, Neil E. Caporaso, Howard J. Edenberg, Clyde Francks, Joel Gelernter, Hans Joergen Grabe, Hyman Hops, Marjo‐Riitta Järvelin, Magnus Johannesson, Kenneth S. Kendler, Terho Lehtimaeki, Patrik K. E. Magnusson, Mary L. Marazita, Jonathan Marchini, Braxton D. Mitchell, Markus M. Nöethen, Brenda W.J.H. Penninx, Olli Raitakari, Marcella Rietschel, Dan Rujescu, Nilesh J. Samani, Ann G. Schwartz, Sanjay Shete, Margaret Spitz, Gary E. Swan, Henry Voelzke, Juha Veijola, Qingyi Wei, Chris Amos, Dale S. Cannon, Richard A. Grucza, Dorothy Hatsukami, Andrew C. 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
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, Pfizer, Tobacco-Related Disease Research Program, National Alliance for Research on Schizophrenia and Depression, National Institute for Health and Care Research, British Heart Foundation, European Commission, Stiftelsen för Strategisk Forskning, Vrije Universiteit Amsterdam, Forskningsrådet för Arbetsliv och Socialvetenskap, Kela, Bundesministerium für Bildung und Forschung, Suomen Kulttuurirahasto, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Juho Vainion Säätiö, Vetenskapsrådet, Emil Aaltosen Säätiö, Alfried Krupp von Bohlen und Halbach-Stiftung, Tampereen Tuberkuloosisäätiö, Paavo Nurmen Säätiö, Turun Yliopistollinen Keskussairaala, Centre for Medical Systems Biology, Ministry of Cultural Affairs, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Center for Research Resources, NIH Clinical Center, FP7 Ideas: European Research Council
Awards: G1077033501, G1535984833, Variants in CHRNA5/CHRNA3/CHRNB4 and nicotine dependence, G3199409182, G3209059653, G3444887196, G357049385, G3655053135, G3687180791, G3868930229, Verbundprojekt: Molekulare Ursachen von Affektiven Störungen und Schizophrenie 'MOODS' -TP 5,6, Genetics of Alcohol Dependence in African-Americans, Anwendung von DNA-Array-Technologien in Molekularer Medizin und Mikrobiologie, Verbesserung der Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, Phase II, G522734742, Mapping Genes for comorbidity of SUDs and Depression, G5732418131, G6029994567, G6087908568, G6091493096, G6144234142, Verbundprojekt: Molekulare Ursachen von Affektiven Störungen und Schizophrenie 'Moods' - Teilprojekt : 1, 3, 4, 6, 7, 9, 12, 14, Genetics of Opioid Dependence, G6413504379, Genetics of Alcohol Dependence in American Populations, G6639498476, G738160294, Beyond the Genetics of Addiction, G7453583093, Washington University Institute of Clinical and Translational Sciences (KL2), G816910144, Genetics of Cocaine Dependence, PERSISTENCE AND CHANGE IN DRINKING HABITS--TWIN STUDY, Verbesserung der Struktur- und Leistungsfähigkeit der klinischen Forschung besonders in den Schwerpunkten Community Medicine und Molekulare Medizin, G9000001730, G9000006138, G9000017353, G9000041718, G9000054071, G9000078609, G9000083019, G9000144655, G9000149999, G9000176579, G9000185064, G9000204396, G9000243987, G9000273886, G9000309104, G9000311828, G915808470
OpenAlex ID: W2951803775