Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking
Authors: Stephens Sarah H. , Hartz Sarah M. , Hoft Nicole R. , Saccone Nancy L. , Corley Robin C. , Hewitt John K. , Hopfer Christian J. , Breslau Naomi , Coon Hilary , Chen Xiangning , Ducci Francesca , Dueker Nicole , Franceschini Nora , Frank Josef , Han Younghun , Hansel Nadia N. , Jiang Chenhui , Korhonen Tellervo , Lind Penelope A. , Liu Jason , Lyytikäinen Leo‐Pekka , Michel Martha , Shaffer John R. , Short Susan E. , Sun Juzhong , Teumer Alexander , Thompson John R. , Vogelzangs Nicole , Vink Jacqueline M. , Wenzlaff Angela , Wheeler William , Yang Bao‐Zhu , Aggen Steven H. , Balmforth Anthony J. , Baumeister Sebastian E. , Beaty Terri H. , Benjamin Daniel J. , Bergen Andrew W. , Broms Ulla , Cesarini David , Chatterjee Nilanjan , Chen Jingchun , Cheng Yu‐Ching , Cichon Sven , Couper David , Cucca Francesco , Dick Danielle , Foroud Tatiana , Furberg Helena , Giegling Ina , Gillespie Nathan A. , Gu Fangyi , Hall Alistair S. , Hällfors Jenni , Han Shizhong , Hartmann Annette M. , Heikkilä Kauko , Hickie Ian B. , Hottenga Jouke Jan , Jousilahti Pekka , Kaakinen Marika , Kähönen Mika , Koellinger Philipp D. , Kittner Stephen , Konte Bettina , Landi Maria‐Teresa , Laatikainen Tiina , Leppert Mark , Levy Steven M. , Mathias Rasika A. , McNeil Daniel W. , Medland Sarah E. , Montgomery Grant W. , Murray Tanda , Nauck Matthias , North Kari E. , Paré Peter D. , Pergadia Michele , Ruczinski Ingo , Salomaa Veikko , Viikari Jorma , Willemsen Gonneke , Barnes Kathleen C. , Boerwinkle Eric , Boomsma Dorret I. , Caporaso Neil , Edenberg Howard J. , Francks Clyde , Gelernter Joel , Grabe Hans Jörgen , Hops Hyman , Jarvelin Marjo‐Riitta , Johannesson Magnus , Kendler Kenneth S. , Lehtimäki Terho , Magnusson Patrik K.E. , Marazita Mary L. , Marchini Jonathan , Mitchell Braxton D. , Nöthen Markus M. , Penninx Brenda W. , Raitakari Olli , Rietschel Marcella , Rujescu Dan , Samani Nilesh J. , Schwartz Ann G. , Shete Sanjay , Spitz Margaret , Swan Gary E. , Völzke Henry , Veijola Juha , Wei Qingyi , Amos Chris , Cannon Dale S. , Grucza Richard , Hatsukami Dorothy , Heath Andrew , Johnson Eric O. , Kaprio Jaakko , Madden Pamela , Martin Nicholas G. , Stevens Victoria L. , Weiss Robert B. , Kraft Peter , Bierut Laura J. , Ehringer Marissa A. 
Published: November 2013

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.