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 N. 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 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 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 A. 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

    Fingerprint

    Multigene Family
    Smoking
    Tobacco Use Disorder
    Phenotype
    Tobacco
    Single Nucleotide Polymorphism
    Meta-Analysis
    Cotinine
    Nicotinic Receptors
    Tobacco Use
    Tobacco Products
    Lung Neoplasms
    Genes

    Keywords

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

    ASJC Scopus subject areas

    • Epidemiology
    • Genetics(clinical)

    Cite this

    Stephens, S. H., Hartz, S. M., Hoft, N. R., Saccone, N. L., Corley, R. C., Hewitt, J. K., ... 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

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

    In: Genetic Epidemiology, Vol. 37, No. 8, 12.2013, p. 846-859.

    Research output: Contribution to journalArticle

    Stephens, SH, Hartz, SM, Hoft, NR, Saccone, NL, Corley, RC, Hewitt, JK, Hopfer, CJ, Breslau, N, Coon, H, Chen, X, Ducci, F, Dueker, N, Franceschini, N, Frank, J, Han, Y, Hansel, NN, Jiang, C, Korhonen, T, Lind, PA, Liu, J, Lyytikäinen, LP, Michel, M, Shaffer, JR, Short, SE, Sun, J, Teumer, A, Thompson, JR, Vogelzangs, N, Vink, JM, Wenzlaff, A, Wheeler, W, Yang, BZ, Aggen, SH, Balmforth, AJ, Baumeister, SE, Beaty, TH, Benjamin, DJ, Bergen, AW, Broms, U, Cesarini, D, Chatterjee, N, Chen, J, Cheng, YC, Cichon, S, Couper, D, Cucca, F, Dick, D, Foroud, T, Furberg, H, Giegling, I, Gillespie, NA, Gu, F, Hall, AS, Hällfors, J, Han, S, Hartmann, AM, Heikkilä, K, Hickie, IB, Hottenga, JJ, Jousilahti, P, Kaakinen, M, Kähönen, M, Koellinger, PD, Kittner, S, Konte, B, Landi, MT, Laatikainen, T, Leppert, M, Levy, SM, Mathias, RA, Mcneil, DW, Medland, SE, Montgomery, GW, Murray, T, Nauck, M, North, KE, Paré, PD, Pergadia, M, Ruczinski, I, Salomaa, V, Viikari, J, Willemsen, G, Barnes, KC, Boerwinkle, E, Boomsma, DI, Caporaso, N, Edenberg, HJ, Francks, C, Gelernter, J, Grabe, HJ, Hops, H, Jarvelin, MR, Johannesson, M, Kendler, KS, Lehtimäki, T, Magnusson, PKE, Marazita, ML, Marchini, J, Mitchell, BD, Nöthen, MM, Penninx, BW, Raitakari, O, Rietschel, M, Rujescu, D, Samani, NJ, Schwartz, AG, Shete, S, Spitz, M, Swan, GE, Völzke, H, Veijola, J, Wei, Q, Amos, C, Cannon, DS, Grucza, R, Hatsukami, D, Heath, A, Johnson, EO, Kaprio, J, Madden, P, Martin, NG, Stevens, VL, Weiss, RB, Kraft, P, Bierut, LJ & Ehringer, MA 2013, 'Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking', Genetic Epidemiology, vol. 37, no. 8, pp. 846-859. https://doi.org/10.1002/gepi.21760
    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. / Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. In: Genetic Epidemiology. 2013 ; Vol. 37, No. 8. pp. 846-859.
    @article{602c553264c943709fca5b09508f5846,
    title = "Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking",
    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.",
    keywords = "CHRNA3, CHRNA5, CHRNB4, Meta-analysis, Nicotine, Smoke",
    author = "Stephens, {Sarah H.} and Hartz, {Sarah M.} and Hoft, {Nicole R.} and Saccone, {Nancy L.} and Corley, {Robin C.} and Hewitt, {John K.} and Hopfer, {Christian J.} and Naomi Breslau and Hilary Coon and Xiangning Chen and Francesca Ducci and Nicole Dueker and Nora Franceschini and Josef Frank and Younghun Han and Hansel, {Nadia N.} and Chenhui Jiang and Tellervo Korhonen and Lind, {Penelope A.} and Jason Liu and Lyytik{\"a}inen, {Leo Pekka} and Martha Michel and Shaffer, {John R.} and Short, {Susan E.} and Juzhong Sun and Alexander Teumer and Thompson, {John R.} and Nicole Vogelzangs and Vink, {Jacqueline M.} and Angela Wenzlaff and William Wheeler and Yang, {Bao Zhu} and Aggen, {Steven H.} and Balmforth, {Anthony J.} and Baumeister, {Sebastian E.} and Beaty, {Terri H.} and Benjamin, {Daniel J.} and Bergen, {Andrew W.} and Ulla Broms and David Cesarini and Nilanjan Chatterjee and Jingchun Chen and Cheng, {Yu Ching} and Sven Cichon and David Couper and Francesco Cucca and Danielle Dick and Tatiana Foroud and Helena Furberg and Ina Giegling and Gillespie, {Nathan A.} and Fangyi Gu and Hall, {Alistair S.} and Jenni H{\"a}llfors and Shizhong Han and Hartmann, {Annette M.} and Kauko Heikkil{\"a} and Hickie, {Ian B.} and Hottenga, {Jouke Jan} and Pekka Jousilahti and Marika Kaakinen and Mika K{\"a}h{\"o}nen and Koellinger, {Philipp D.} and Stephen Kittner and Bettina Konte and Landi, {Maria Teresa} and Tiina Laatikainen and Mark Leppert and Levy, {Steven M.} and Mathias, {Rasika A.} and Mcneil, {Daniel W.} and Medland, {Sarah E.} and Montgomery, {Grant W.} and Tanda Murray and Matthias Nauck and North, {Kari E.} and Par{\'e}, {Peter D.} and Michele Pergadia and Ingo Ruczinski and Veikko Salomaa and Jorma Viikari and Gonneke Willemsen and Barnes, {Kathleen C.} and Eric Boerwinkle and Boomsma, {Dorret I.} and Neil Caporaso and Edenberg, {Howard J.} and Clyde Francks and Joel Gelernter and Grabe, {Hans J{\"o}rgen} and Hyman Hops and Jarvelin, {Marjo Riitta} and Magnus Johannesson and Kendler, {Kenneth S.} and Terho Lehtim{\"a}ki and Magnusson, {Patrik K E} and Marazita, {Mary L.} and Jonathan Marchini and Mitchell, {Braxton D.} and N{\"o}then, {Markus M.} and Penninx, {Brenda W.} and Olli Raitakari and Marcella Rietschel and Dan Rujescu and Samani, {Nilesh J.} and Schwartz, {Ann G.} and Sanjay Shete and Margaret Spitz and Swan, {Gary E.} and Henry V{\"o}lzke and Juha Veijola and Qingyi Wei and Chris Amos and Cannon, {Dale S.} and Richard Grucza and Dorothy Hatsukami and Andrew Heath and Johnson, {Eric O.} and Jaakko Kaprio and Pamela Madden and Martin, {Nicholas G.} and Stevens, {Victoria L.} and Weiss, {Robert B.} and Peter Kraft and Bierut, {Laura J.} and Ehringer, {Marissa A.}",
    year = "2013",
    month = "12",
    doi = "10.1002/gepi.21760",
    language = "English (US)",
    volume = "37",
    pages = "846--859",
    journal = "Genetic Epidemiology",
    issn = "0741-0395",
    publisher = "Wiley-Liss Inc.",
    number = "8",

    }

    TY - JOUR

    T1 - Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking

    AU - Stephens, Sarah H.

    AU - Hartz, Sarah M.

    AU - Hoft, Nicole R.

    AU - Saccone, Nancy L.

    AU - Corley, Robin C.

    AU - Hewitt, John K.

    AU - Hopfer, Christian J.

    AU - Breslau, Naomi

    AU - Coon, Hilary

    AU - Chen, Xiangning

    AU - Ducci, Francesca

    AU - Dueker, Nicole

    AU - Franceschini, Nora

    AU - Frank, Josef

    AU - Han, Younghun

    AU - Hansel, Nadia N.

    AU - Jiang, Chenhui

    AU - Korhonen, Tellervo

    AU - Lind, Penelope A.

    AU - Liu, Jason

    AU - Lyytikäinen, Leo Pekka

    AU - Michel, Martha

    AU - Shaffer, John R.

    AU - Short, Susan E.

    AU - Sun, Juzhong

    AU - Teumer, Alexander

    AU - Thompson, John R.

    AU - Vogelzangs, Nicole

    AU - Vink, Jacqueline M.

    AU - Wenzlaff, Angela

    AU - Wheeler, William

    AU - Yang, Bao Zhu

    AU - Aggen, Steven H.

    AU - Balmforth, Anthony J.

    AU - Baumeister, Sebastian E.

    AU - Beaty, Terri H.

    AU - Benjamin, Daniel J.

    AU - Bergen, Andrew W.

    AU - Broms, Ulla

    AU - Cesarini, David

    AU - Chatterjee, Nilanjan

    AU - Chen, Jingchun

    AU - Cheng, Yu Ching

    AU - Cichon, Sven

    AU - Couper, David

    AU - Cucca, Francesco

    AU - Dick, Danielle

    AU - Foroud, Tatiana

    AU - Furberg, Helena

    AU - Giegling, Ina

    AU - Gillespie, Nathan A.

    AU - Gu, Fangyi

    AU - Hall, Alistair S.

    AU - Hällfors, Jenni

    AU - Han, Shizhong

    AU - Hartmann, Annette M.

    AU - Heikkilä, Kauko

    AU - Hickie, Ian B.

    AU - Hottenga, Jouke Jan

    AU - Jousilahti, Pekka

    AU - Kaakinen, Marika

    AU - Kähönen, Mika

    AU - Koellinger, Philipp D.

    AU - Kittner, Stephen

    AU - Konte, Bettina

    AU - Landi, Maria Teresa

    AU - Laatikainen, Tiina

    AU - Leppert, Mark

    AU - Levy, Steven M.

    AU - Mathias, Rasika A.

    AU - Mcneil, Daniel W.

    AU - Medland, Sarah E.

    AU - Montgomery, Grant W.

    AU - Murray, Tanda

    AU - Nauck, Matthias

    AU - North, Kari E.

    AU - Paré, Peter D.

    AU - Pergadia, Michele

    AU - Ruczinski, Ingo

    AU - Salomaa, Veikko

    AU - Viikari, Jorma

    AU - Willemsen, Gonneke

    AU - Barnes, Kathleen C.

    AU - Boerwinkle, Eric

    AU - Boomsma, Dorret I.

    AU - Caporaso, Neil

    AU - Edenberg, Howard J.

    AU - Francks, Clyde

    AU - Gelernter, Joel

    AU - Grabe, Hans Jörgen

    AU - Hops, Hyman

    AU - Jarvelin, Marjo Riitta

    AU - Johannesson, Magnus

    AU - Kendler, Kenneth S.

    AU - Lehtimäki, Terho

    AU - Magnusson, Patrik K E

    AU - Marazita, Mary L.

    AU - Marchini, Jonathan

    AU - Mitchell, Braxton D.

    AU - Nöthen, Markus M.

    AU - Penninx, Brenda W.

    AU - Raitakari, Olli

    AU - Rietschel, Marcella

    AU - Rujescu, Dan

    AU - Samani, Nilesh J.

    AU - Schwartz, Ann G.

    AU - Shete, Sanjay

    AU - Spitz, Margaret

    AU - Swan, Gary E.

    AU - Völzke, Henry

    AU - Veijola, Juha

    AU - Wei, Qingyi

    AU - Amos, Chris

    AU - Cannon, Dale S.

    AU - Grucza, Richard

    AU - Hatsukami, Dorothy

    AU - Heath, Andrew

    AU - Johnson, Eric O.

    AU - Kaprio, Jaakko

    AU - Madden, Pamela

    AU - Martin, Nicholas G.

    AU - Stevens, Victoria L.

    AU - Weiss, Robert B.

    AU - Kraft, Peter

    AU - Bierut, Laura J.

    AU - Ehringer, Marissa A.

    PY - 2013/12

    Y1 - 2013/12

    N2 - 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.

    AB - 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.

    KW - CHRNA3

    KW - CHRNA5

    KW - CHRNB4

    KW - Meta-analysis

    KW - Nicotine

    KW - Smoke

    UR - http://www.scopus.com/inward/record.url?scp=84887606484&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84887606484&partnerID=8YFLogxK

    U2 - 10.1002/gepi.21760

    DO - 10.1002/gepi.21760

    M3 - Article

    C2 - 24186853

    AN - SCOPUS:84887606484

    VL - 37

    SP - 846

    EP - 859

    JO - Genetic Epidemiology

    JF - Genetic Epidemiology

    SN - 0741-0395

    IS - 8

    ER -