Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E. Thorgeirsson; Daniel F. Gudbjartsson; Ida Surakka; Jacqueline M. Vink; Najaf Amin; Frank Geller; Patrick Sulem; Thorunn Rafnar; Tonu Esko; Stefan Walter; Christian Gieger; Rajesh Rawal; Massimo Mangino; Inga Prokopenko; Reedik Maegi; Kaisu Keskitalo; Iris H. Gudjonsdottir; Solveig Gretarsdottir; Hreinn Stefansson; John R. Thompson; Yurii S. Aulchenko; Mari Nelis; Katja K. Aben; Martin den Heijer; Asger Dirksen; Haseem Ashraf; Nicole Soranzo; Ana M. Valdes; Claire Steves; Andre G. Uitterlinden; Albert Hofman; Anke Toenjes; Peter Kovacs; Jouke Jan Hottenga; Gonneke Willemsen; Nicole Vogelzangs; Angela Doering; Norbert Dahmen; Barbara Nitz; Michele L. Pergadia; Berta Saez; Veronica De Diego; Victoria Lezcano; Maria D. Garcia-Prats; Samuli Ripatti; Markus Perola; Johannes Kettunen; Anna-Liisa Hartikainen; Anneli Pouta; Jaana Laitinen; Matti Isohanni; Shen Huei-Yi; Maxine Allen; Maria Krestyaninova; Alistair S. Hall; Gregory T. Jones; Andre M. van Rij; Thomas Mueller; Benjamin Dieplinger; Meinhard Haltmayer; Steinn Jonsson; Stefan E. Matthiasson; Hogni Oskarsson; Thorarinn Tyrfingsson; Lambertus A. Kiemeney; Jose I. Mayordomo; Jes S. Lindholt; Jesper Holst Pedersen; Wilbur A. Franklin; Holly Wolf; Grant W. Montgomery; Andrew C. Heath; Nicholas G. Martin; Pamela A. F. Madden; Ina Giegling; Dan Rujescu; Marjo-Riitta Jaervelin; Veikko Salomaa; Michael Stumvoll; Tim D. Spector; H-Erich Wichmann; Andres Metspalu; Nilesh J. Samani; Brenda W. Penninx; Ben A. Oostra; Dorret I. Boomsma; Henning Tiemeier; Cornelia M. van Duijn; Jaakko Kaprio; Jeffrey R. Gulcher; Mark I. McCarthy; Leena Peltonen; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1038/ng.573

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E. Thorgeirsson, Daniel F. Gudbjartsson, Ida Surakka, Jacqueline M. Vink, Najaf Amin, Frank Geller, Patrick Sulem, Thorunn Rafnar, Tonu Esko, Stefan Walter, Christian Gieger, Rajesh Rawal, Massimo Mangino, Inga Prokopenko, Reedik Maegi, Kaisu Keskitalo, Iris H. Gudjonsdottir, Solveig Gretarsdottir, Hreinn Stefansson, John R. ThompsonYurii S. Aulchenko, Mari Nelis, Katja K. Aben, Martin den Heijer, Asger Dirksen, Haseem Ashraf, Nicole Soranzo, Ana M. Valdes, Claire Steves, Andre G. Uitterlinden, Albert Hofman, Anke Toenjes, Peter Kovacs, Jouke Jan Hottenga, Gonneke Willemsen, Nicole Vogelzangs, Angela Doering, Norbert Dahmen, Barbara Nitz, Michele L. Pergadia, Berta Saez, Veronica De Diego, Victoria Lezcano, Maria D. Garcia-Prats, Samuli Ripatti, Markus Perola, Johannes Kettunen, Anna-Liisa Hartikainen, Anneli Pouta, Jaana Laitinen, Matti Isohanni, Shen Huei-Yi, Maxine Allen, Maria Krestyaninova, Alistair S. Hall, Gregory T. Jones, Andre M. van Rij, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E. Matthiasson, Hogni Oskarsson, Thorarinn Tyrfingsson, Lambertus A. Kiemeney, Jose I. Mayordomo, Jes S. Lindholt, Jesper Holst Pedersen, Wilbur A. Franklin, Holly Wolf, Grant W. Montgomery, Andrew C. Heath, Nicholas G. Martin, Pamela A. F. Madden, Ina Giegling, Dan Rujescu, Marjo-Riitta Jaervelin, Veikko Salomaa, Michael Stumvoll, Tim D. Spector, H-Erich Wichmann, Andres Metspalu, Nilesh J. Samani, Brenda W. Penninx, Ben A. Oostra, Dorret I. Boomsma, Henning Tiemeier, Cornelia M. van Duijn, Jaakko Kaprio, Jeffrey R. Gulcher, Mark I. McCarthy, Leena Peltonen, Unnur Thorsteinsdottir, Kari Stefansson

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Abstract

Smoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P <5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2-4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

Original language	English
Pages (from-to)	448 - U135
Number of pages	6
Journal	Nature Genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.573
Publication status	Published - May 2010

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Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I., Vink, J. M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., Mangino, M., Prokopenko, I., Maegi, R., Keskitalo, K., Gudjonsdottir, I. H., Gretarsdottir, S., Stefansson, H., ... Stefansson, K. (2010). Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nature Genetics, 42(5), 448 - U135. https://doi.org/10.1038/ng.573

@article{18af042375744d129c92a0e9bc937234,

title = "Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior",

abstract = "Smoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P <5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2-4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).",

author = "Thorgeirsson, {Thorgeir E.} and Gudbjartsson, {Daniel F.} and Ida Surakka and Vink, {Jacqueline M.} and Najaf Amin and Frank Geller and Patrick Sulem and Thorunn Rafnar and Tonu Esko and Stefan Walter and Christian Gieger and Rajesh Rawal and Massimo Mangino and Inga Prokopenko and Reedik Maegi and Kaisu Keskitalo and Gudjonsdottir, {Iris H.} and Solveig Gretarsdottir and Hreinn Stefansson and Thompson, {John R.} and Aulchenko, {Yurii S.} and Mari Nelis and Aben, {Katja K.} and {den Heijer}, Martin and Asger Dirksen and Haseem Ashraf and Nicole Soranzo and Valdes, {Ana M.} and Claire Steves and Uitterlinden, {Andre G.} and Albert Hofman and Anke Toenjes and Peter Kovacs and Hottenga, {Jouke Jan} and Gonneke Willemsen and Nicole Vogelzangs and Angela Doering and Norbert Dahmen and Barbara Nitz and Pergadia, {Michele L.} and Berta Saez and {De Diego}, Veronica and Victoria Lezcano and Garcia-Prats, {Maria D.} and Samuli Ripatti and Markus Perola and Johannes Kettunen and Anna-Liisa Hartikainen and Anneli Pouta and Jaana Laitinen and Matti Isohanni and Shen Huei-Yi and Maxine Allen and Maria Krestyaninova and Hall, {Alistair S.} and Jones, {Gregory T.} and {van Rij}, {Andre M.} and Thomas Mueller and Benjamin Dieplinger and Meinhard Haltmayer and Steinn Jonsson and Matthiasson, {Stefan E.} and Hogni Oskarsson and Thorarinn Tyrfingsson and Kiemeney, {Lambertus A.} and Mayordomo, {Jose I.} and Lindholt, {Jes S.} and Pedersen, {Jesper Holst} and Franklin, {Wilbur A.} and Holly Wolf and Montgomery, {Grant W.} and Heath, {Andrew C.} and Martin, {Nicholas G.} and Madden, {Pamela A. F.} and Ina Giegling and Dan Rujescu and Marjo-Riitta Jaervelin and Veikko Salomaa and Michael Stumvoll and Spector, {Tim D.} and H-Erich Wichmann and Andres Metspalu and Samani, {Nilesh J.} and Penninx, {Brenda W.} and Oostra, {Ben A.} and Boomsma, {Dorret I.} and Henning Tiemeier and {van Duijn}, {Cornelia M.} and Jaakko Kaprio and Gulcher, {Jeffrey R.} and McCarthy, {Mark I.} and Leena Peltonen and Unnur Thorsteinsdottir and Kari Stefansson",

year = "2010",

month = may,

doi = "10.1038/ng.573",

language = "English",

volume = "42",

pages = "448 -- U135",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Research",

number = "5",

}

Thorgeirsson, TE, Gudbjartsson, DF, Surakka, I, Vink, JM, Amin, N, Geller, F, Sulem, P, Rafnar, T, Esko, T, Walter, S, Gieger, C, Rawal, R, Mangino, M, Prokopenko, I, Maegi, R, Keskitalo, K, Gudjonsdottir, IH, Gretarsdottir, S, Stefansson, H, Thompson, JR, Aulchenko, YS, Nelis, M, Aben, KK, den Heijer, M, Dirksen, A, Ashraf, H, Soranzo, N, Valdes, AM , Steves, C, Uitterlinden, AG, Hofman, A, Toenjes, A, Kovacs, P, Hottenga, JJ, Willemsen, G, Vogelzangs, N, Doering, A, Dahmen, N, Nitz, B, Pergadia, ML, Saez, B, De Diego, V, Lezcano, V, Garcia-Prats, MD, Ripatti, S, Perola, M, Kettunen, J, Hartikainen, A-L, Pouta, A, Laitinen, J, Isohanni, M, Huei-Yi, S, Allen, M, Krestyaninova, M, Hall, AS, Jones, GT, van Rij, AM, Mueller, T, Dieplinger, B, Haltmayer, M, Jonsson, S, Matthiasson, SE, Oskarsson, H, Tyrfingsson, T, Kiemeney, LA, Mayordomo, JI, Lindholt, JS, Pedersen, JH, Franklin, WA, Wolf, H, Montgomery, GW, Heath, AC, Martin, NG, Madden, PAF, Giegling, I, Rujescu, D, Jaervelin, M-R, Salomaa, V, Stumvoll, M, Spector, TD, Wichmann, H-E, Metspalu, A, Samani, NJ, Penninx, BW, Oostra, BA, Boomsma, DI, Tiemeier, H, van Duijn, CM, Kaprio, J, Gulcher, JR, McCarthy, MI, Peltonen, L, Thorsteinsdottir, U & Stefansson, K 2010, 'Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior', Nature Genetics, vol. 42, no. 5, pp. 448 - U135. https://doi.org/10.1038/ng.573

TY - JOUR

T1 - Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

AU - Thorgeirsson, Thorgeir E.

AU - Gudbjartsson, Daniel F.

AU - Surakka, Ida

AU - Vink, Jacqueline M.

AU - Amin, Najaf

AU - Geller, Frank

AU - Sulem, Patrick

AU - Rafnar, Thorunn

AU - Esko, Tonu

AU - Walter, Stefan

AU - Gieger, Christian

AU - Rawal, Rajesh

AU - Mangino, Massimo

AU - Prokopenko, Inga

AU - Maegi, Reedik

AU - Keskitalo, Kaisu

AU - Gudjonsdottir, Iris H.

AU - Gretarsdottir, Solveig

AU - Stefansson, Hreinn

AU - Thompson, John R.

AU - Aulchenko, Yurii S.

AU - Nelis, Mari

AU - Aben, Katja K.

AU - den Heijer, Martin

AU - Dirksen, Asger

AU - Ashraf, Haseem

AU - Soranzo, Nicole

AU - Valdes, Ana M.

AU - Steves, Claire

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Toenjes, Anke

AU - Kovacs, Peter

AU - Hottenga, Jouke Jan

AU - Willemsen, Gonneke

AU - Vogelzangs, Nicole

AU - Doering, Angela

AU - Dahmen, Norbert

AU - Nitz, Barbara

AU - Pergadia, Michele L.

AU - Saez, Berta

AU - De Diego, Veronica

AU - Lezcano, Victoria

AU - Garcia-Prats, Maria D.

AU - Ripatti, Samuli

AU - Perola, Markus

AU - Kettunen, Johannes

AU - Hartikainen, Anna-Liisa

AU - Pouta, Anneli

AU - Laitinen, Jaana

AU - Isohanni, Matti

AU - Huei-Yi, Shen

AU - Allen, Maxine

AU - Krestyaninova, Maria

AU - Hall, Alistair S.

AU - Jones, Gregory T.

AU - van Rij, Andre M.

AU - Mueller, Thomas

AU - Dieplinger, Benjamin

AU - Haltmayer, Meinhard

AU - Jonsson, Steinn

AU - Matthiasson, Stefan E.

AU - Oskarsson, Hogni

AU - Tyrfingsson, Thorarinn

AU - Kiemeney, Lambertus A.

AU - Mayordomo, Jose I.

AU - Lindholt, Jes S.

AU - Pedersen, Jesper Holst

AU - Franklin, Wilbur A.

AU - Wolf, Holly

AU - Montgomery, Grant W.

AU - Heath, Andrew C.

AU - Martin, Nicholas G.

AU - Madden, Pamela A. F.

AU - Giegling, Ina

AU - Rujescu, Dan

AU - Jaervelin, Marjo-Riitta

AU - Salomaa, Veikko

AU - Stumvoll, Michael

AU - Spector, Tim D.

AU - Wichmann, H-Erich

AU - Metspalu, Andres

AU - Samani, Nilesh J.

AU - Penninx, Brenda W.

AU - Oostra, Ben A.

AU - Boomsma, Dorret I.

AU - Tiemeier, Henning

AU - van Duijn, Cornelia M.

AU - Kaprio, Jaakko

AU - Gulcher, Jeffrey R.

AU - McCarthy, Mark I.

AU - Peltonen, Leena

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

PY - 2010/5

Y1 - 2010/5

N2 - Smoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P <5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2-4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

AB - Smoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P <5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2-4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

U2 - 10.1038/ng.573

DO - 10.1038/ng.573

M3 - Article

SN - 1546-1718

VL - 42

SP - 448 - U135

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

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