Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

S.H. Stephens; S.M. Hartz; N.R. Hoft; N.L. Saccone; R.C. Corley; J.K. Hewitt; C.J. Hopfer; N. Breslau; H. Coon; X. Chen; F. Ducci; N. Dueker; N. Franceschini; J. Frank; Y. Han; N.N. Hansel; C. Jiang; T. Korhonen; P.A. Lind; J. Liu; L.P. Lyytikäinen; M. Michel; J.R. Shaffer; S.E. Short; J. Sun; A. Teumer; J.R. Thompson; N. Vogelzangs; J.M. Vink; A.S. Wenzlaff; W. Wheeler; B.Z. Yang; S.H. Aggen; A.J. Balmforth; S.E. Baumeister; T. Beaty; D.J. Benjamin; A.W. Bergen; U. Broms; D. Cesarini; N. Chatterjee; J. Chen; Y.C. Cheng; S. Cichon; D. Couper; F. Cucca; D. Dick; T. Foroud; H. Furberg; I. Giegling; N.A. Gillespie; F. Gu; A.S. Hall; J. Hällfors; S. Han; A.M. Hartmann; K. Heikkilä; I.B. Hickie; J.J. Hottenga; P. Jousilahti; M. Kaakinen; M. Kähönen; P.D. Koellinger; S.J. Kittner; B. Konte; M.T. Landi; T. Laatikainen; M. Leppert; S.M. Levy; R.A. Mathias; D.W. McNeil; S.E. Medland; G.W. Montgomery; T. Murray; M. Nauck; K.E. North; P.D. Paré; M.L. Pergadia; I. Ruczinski; V. Salomaa; J. Viikari; G. Willemsen; K.C. Barnes; E. Boerwinkle; D.I. Boomsma; N. Caporaso; H.J. Edenberg; C. Francks; J. Gelernter; H.J. Grabe; H. Hops; M.R. Järvelin; M. Johannesson; K.S. Kendler; T. Lehtimäki; P.K.E. Magnusson; M.L. Marazita; J. Marchini; B.D. Mitchell; M.M. Nöthen; B.W.J.H. Penninx; O. Raitakari; M. Rietschel; D. Rujescu; N.J. Samani; A.G. Schwartz; S. Shete; M. Spitz; G.E. Swan; H. Völzke; J. Veijola; Q. Wei; C.I. Amos; D.S. Cannon; R.A. Grucza; D. Hatsukami; A.C. Heath; E.O. Johnson; J. Kaprio; P.A.F. Madden; N.G. Martin; V.L. Stevens; R.B. Weiss; P. Kraft; L.J. Bierut; M. Ehringer

doi:10.1002/gepi.21760

Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

S.H. Stephens, S.M. Hartz, N.R. Hoft, N.L. Saccone, R.C. Corley, J.K. Hewitt, C.J. Hopfer, N. Breslau, H. Coon, X. Chen, F. Ducci, N. Dueker, N. Franceschini, J. Frank, Y. Han, N.N. Hansel, C. Jiang, T. Korhonen, P.A. Lind, J. LiuL.P. Lyytikäinen, M. Michel, J.R. Shaffer, S.E. Short, J. Sun, A. Teumer, J.R. Thompson, N. Vogelzangs, J.M. Vink, A.S. Wenzlaff, W. Wheeler, B.Z. Yang, S.H. Aggen, A.J. Balmforth, S.E. Baumeister, T. Beaty, D.J. Benjamin, A.W. Bergen, U. Broms, D. Cesarini, N. Chatterjee, J. Chen, Y.C. Cheng, S. Cichon, D. Couper, F. Cucca, D. Dick, T. Foroud, H. Furberg, I. Giegling, N.A. Gillespie, F. Gu, A.S. Hall, J. Hällfors, S. Han, A.M. Hartmann, K. Heikkilä, I.B. Hickie, J.J. Hottenga, P. Jousilahti, M. Kaakinen, M. Kähönen, P.D. Koellinger, S.J. Kittner, B. Konte, M.T. Landi, T. Laatikainen, M. Leppert, S.M. Levy, R.A. Mathias, D.W. McNeil, S.E. Medland, G.W. Montgomery, T. Murray, M. Nauck, K.E. North, P.D. Paré, M.L. Pergadia, I. Ruczinski, V. Salomaa, J. Viikari, G. Willemsen, K.C. Barnes, E. Boerwinkle, D.I. Boomsma, N. Caporaso, H.J. Edenberg, C. Francks, J. Gelernter, H.J. Grabe, H. Hops, M.R. Järvelin, M. Johannesson, K.S. Kendler, T. Lehtimäki, P.K.E. Magnusson, M.L. Marazita, J. Marchini, B.D. Mitchell, M.M. Nöthen, B.W.J.H. Penninx, O. Raitakari, M. Rietschel, D. Rujescu, N.J. Samani, A.G. Schwartz, S. Shete, M. Spitz, G.E. Swan, H. Völzke, J. Veijola, Q. Wei, C.I. Amos, D.S. Cannon, R.A. Grucza, D. Hatsukami, A.C. Heath, E.O. Johnson, J. Kaprio, P.A.F. Madden, N.G. Martin, V.L. Stevens, R.B. Weiss, P. Kraft, L.J. Bierut, M. Ehringer

Research output: Contribution to Journal › Article › Academic › peer-review

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. © 2013 WILEY PERIODICALS, INC.

Original language	English
Pages (from-to)	846-859
Journal	Genetic Epidemiology
Volume	37
Issue number	8
DOIs	https://doi.org/10.1002/gepi.21760
Publication status	Published - 2013

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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. N., Jiang, C., Korhonen, T., Lind, P. A., ... Ehringer, M. (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

@article{29b704d6b2684a2f8fb8d0b5220af23b,

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. {\textcopyright} 2013 WILEY PERIODICALS, INC.",

author = "S.H. Stephens and S.M. Hartz and N.R. Hoft and N.L. Saccone and R.C. Corley and J.K. Hewitt and C.J. Hopfer and N. Breslau and H. Coon and X. Chen and F. Ducci and N. Dueker and N. Franceschini and J. Frank and Y. Han and N.N. Hansel and C. Jiang and T. Korhonen and P.A. Lind and J. Liu and L.P. Lyytik{\"a}inen and M. Michel and J.R. Shaffer and S.E. Short and J. Sun and A. Teumer and J.R. Thompson and N. Vogelzangs and J.M. Vink and A.S. Wenzlaff and W. Wheeler and B.Z. Yang and S.H. Aggen and A.J. Balmforth and S.E. Baumeister and T. Beaty and D.J. Benjamin and A.W. Bergen and U. Broms and D. Cesarini and N. Chatterjee and J. Chen and Y.C. Cheng and S. Cichon and D. Couper and F. Cucca and D. Dick and T. Foroud and H. Furberg and I. Giegling and N.A. Gillespie and F. Gu and A.S. Hall and J. H{\"a}llfors and S. Han and A.M. Hartmann and K. Heikkil{\"a} and I.B. Hickie and J.J. Hottenga and P. Jousilahti and M. Kaakinen and M. K{\"a}h{\"o}nen and P.D. Koellinger and S.J. Kittner and B. Konte and M.T. Landi and T. Laatikainen and M. Leppert and S.M. Levy and R.A. Mathias and D.W. McNeil and S.E. Medland and G.W. Montgomery and T. Murray and M. Nauck and K.E. North and P.D. Par{\'e} and M.L. Pergadia and I. Ruczinski and V. Salomaa and J. Viikari and G. Willemsen and K.C. Barnes and E. Boerwinkle and D.I. Boomsma and N. Caporaso and H.J. Edenberg and C. Francks and J. Gelernter and H.J. Grabe and H. Hops and M.R. J{\"a}rvelin and M. Johannesson and K.S. Kendler and T. Lehtim{\"a}ki and P.K.E. Magnusson and M.L. Marazita and J. Marchini and B.D. Mitchell and M.M. N{\"o}then and B.W.J.H. Penninx and O. Raitakari and M. Rietschel and D. Rujescu and N.J. Samani and A.G. Schwartz and S. Shete and M. Spitz and G.E. Swan and H. V{\"o}lzke and J. Veijola and Q. Wei and C.I. Amos and D.S. Cannon and R.A. Grucza and D. Hatsukami and A.C. Heath and E.O. Johnson and J. Kaprio and P.A.F. Madden and N.G. Martin and V.L. Stevens and R.B. Weiss and P. Kraft and L.J. Bierut and M. Ehringer",

year = "2013",

doi = "10.1002/gepi.21760",

language = "English",

volume = "37",

pages = "846--859",

journal = "Genetic Epidemiology",

issn = "0741-0395",

publisher = "Wiley-Liss Inc.",

number = "8",

}

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, AS, Wheeler, W, Yang, BZ, Aggen, SH, Balmforth, AJ, Baumeister, SE, Beaty, T, 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, SJ, 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, ML, 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, Järvelin, MR, Johannesson, M, Kendler, KS, Lehtimäki, T, Magnusson, PKE, Marazita, ML, Marchini, J, Mitchell, BD, Nöthen, MM, Penninx, BWJH, Raitakari, O, Rietschel, M, Rujescu, D, Samani, NJ, Schwartz, AG, Shete, S, Spitz, M, Swan, GE, Völzke, H, Veijola, J, Wei, Q, Amos, CI, Cannon, DS, Grucza, RA, Hatsukami, D, Heath, AC, Johnson, EO, Kaprio, J, Madden, PAF, Martin, NG, Stevens, VL, Weiss, RB, Kraft, P, Bierut, LJ & Ehringer, M 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

TY - JOUR

T1 - Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

AU - Stephens, S.H.

AU - Hartz, S.M.

AU - Hoft, N.R.

AU - Saccone, N.L.

AU - Corley, R.C.

AU - Hewitt, J.K.

AU - Hopfer, C.J.

AU - Breslau, N.

AU - Coon, H.

AU - Chen, X.

AU - Ducci, F.

AU - Dueker, N.

AU - Franceschini, N.

AU - Frank, J.

AU - Han, Y.

AU - Hansel, N.N.

AU - Jiang, C.

AU - Korhonen, T.

AU - Lind, P.A.

AU - Liu, J.

AU - Lyytikäinen, L.P.

AU - Michel, M.

AU - Shaffer, J.R.

AU - Short, S.E.

AU - Sun, J.

AU - Teumer, A.

AU - Thompson, J.R.

AU - Vogelzangs, N.

AU - Vink, J.M.

AU - Wenzlaff, A.S.

AU - Wheeler, W.

AU - Yang, B.Z.

AU - Aggen, S.H.

AU - Balmforth, A.J.

AU - Baumeister, S.E.

AU - Beaty, T.

AU - Benjamin, D.J.

AU - Bergen, A.W.

AU - Broms, U.

AU - Cesarini, D.

AU - Chatterjee, N.

AU - Chen, J.

AU - Cheng, Y.C.

AU - Cichon, S.

AU - Couper, D.

AU - Cucca, F.

AU - Dick, D.

AU - Foroud, T.

AU - Furberg, H.

AU - Giegling, I.

AU - Gillespie, N.A.

AU - Gu, F.

AU - Hall, A.S.

AU - Hällfors, J.

AU - Han, S.

AU - Hartmann, A.M.

AU - Heikkilä, K.

AU - Hickie, I.B.

AU - Hottenga, J.J.

AU - Jousilahti, P.

AU - Kaakinen, M.

AU - Kähönen, M.

AU - Koellinger, P.D.

AU - Kittner, S.J.

AU - Konte, B.

AU - Landi, M.T.

AU - Laatikainen, T.

AU - Leppert, M.

AU - Levy, S.M.

AU - Mathias, R.A.

AU - McNeil, D.W.

AU - Medland, S.E.

AU - Montgomery, G.W.

AU - Murray, T.

AU - Nauck, M.

AU - North, K.E.

AU - Paré, P.D.

AU - Pergadia, M.L.

AU - Ruczinski, I.

AU - Salomaa, V.

AU - Viikari, J.

AU - Willemsen, G.

AU - Barnes, K.C.

AU - Boerwinkle, E.

AU - Boomsma, D.I.

AU - Caporaso, N.

AU - Edenberg, H.J.

AU - Francks, C.

AU - Gelernter, J.

AU - Grabe, H.J.

AU - Hops, H.

AU - Järvelin, M.R.

AU - Johannesson, M.

AU - Kendler, K.S.

AU - Lehtimäki, T.

AU - Magnusson, P.K.E.

AU - Marazita, M.L.

AU - Marchini, J.

AU - Mitchell, B.D.

AU - Nöthen, M.M.

AU - Penninx, B.W.J.H.

AU - Raitakari, O.

AU - Rietschel, M.

AU - Rujescu, D.

AU - Samani, N.J.

AU - Schwartz, A.G.

AU - Shete, S.

AU - Spitz, M.

AU - Swan, G.E.

AU - Völzke, H.

AU - Veijola, J.

AU - Wei, Q.

AU - Amos, C.I.

AU - Cannon, D.S.

AU - Grucza, R.A.

AU - Hatsukami, D.

AU - Heath, A.C.

AU - Johnson, E.O.

AU - Kaprio, J.

AU - Madden, P.A.F.

AU - Martin, N.G.

AU - Stevens, V.L.

AU - Weiss, R.B.

AU - Kraft, P.

AU - Bierut, L.J.

AU - Ehringer, M.

PY - 2013

Y1 - 2013

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. © 2013 WILEY PERIODICALS, INC.

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. © 2013 WILEY PERIODICALS, INC.

U2 - 10.1002/gepi.21760

DO - 10.1002/gepi.21760

M3 - Article

SN - 0741-0395

VL - 37

SP - 846

EP - 859

JO - Genetic Epidemiology

JF - Genetic Epidemiology

IS - 8

ER -

Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

Abstract

Cohort Studies

UN SDGs

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