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 Liu & 106 others Leo 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 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

23 Citations (Scopus)

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
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

  • Genetics(clinical)
  • Epidemiology

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; 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, H, 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 ; 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.
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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.",
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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 Howard Edenberg 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",
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language = "English",
volume = "37",
pages = "846--859",
journal = "Genetic Epidemiology",
issn = "0741-0395",
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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

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

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U2 - 10.1002/gepi.21760

DO - 10.1002/gepi.21760

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SP - 846

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JF - Genetic Epidemiology

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