Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E. Thorgeirsson; Daniel F. Gudbjartsson; Ida Liisa 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 Olli Ripatti; Markus Perola; Johannes Kettunen; Huei-Yi Shen; Jaakko Kaprio; Leena Palotie; ENGAGE Consortium

doi:10.1038/ng.573

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E. Thorgeirsson, Daniel F. Gudbjartsson, Ida Liisa 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 Olli Ripatti, Markus Perola, Johannes Kettunen, Huei-Yi Shen, Jaakko Kaprio, Leena Palotie, ENGAGE Consortium

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

Sammanfattning

Smoking is a common risk factor for many diseases. 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 dependence. 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).

Originalspråk	engelska
Tidskrift	Nature Genetics
Volym	42
Sidor (från-till)	448-453
Antal sidor	6
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.573
Status	Publicerad - 2010
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

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10.1038/ng.573

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Thorgeirsson, T. E., Gudbjartsson, D. F., Surakka, I. L., 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., ... ENGAGE Consortium (2010). Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nature Genetics, 42, 448-453. https://doi.org/10.1038/ng.573

Thorgeirsson, Thorgeir E. ; Gudbjartsson, Daniel F. ; Surakka, Ida Liisa ; Vink, Jacqueline M. ; Amin, Najaf ; Geller, Frank ; Sulem, Patrick ; Rafnar, Thorunn ; Esko, Tonu ; Walter, Stefan ; Gieger, Christian ; Rawal, Rajesh ; Mangino, Massimo ; Prokopenko, Inga ; Maegi, Reedik ; Keskitalo, Kaisu ; Gudjonsdottir, Iris H. ; Gretarsdottir, Solveig ; Stefansson, Hreinn ; Thompson, John R. ; Aulchenko, Yurii S. ; Nelis, Mari ; Aben, Katja K. ; den Heijer, Martin ; Dirksen, Asger ; Ashraf, Haseem ; Soranzo, Nicole ; Valdes, Ana M. ; Steves, Claire ; Uitterlinden, Andre G. ; Hofman, Albert ; Toenjes, Anke ; Kovacs, Peter ; Hottenga, Jouke Jan ; Willemsen, Gonneke ; Vogelzangs, Nicole ; Doering, Angela ; Dahmen, Norbert ; Nitz, Barbara ; Pergadia, Michele L. ; Saez, Berta ; De Diego, Veronica ; Lezcano, Victoria ; Garcia-Prats, Maria D. ; Ripatti, Samuli Olli ; Perola, Markus ; Kettunen, Johannes ; Shen, Huei-Yi ; Kaprio, Jaakko ; Palotie, Leena ; ENGAGE Consortium. / Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. I: Nature Genetics. 2010 ; Vol. 42. s. 448-453.

@article{8270de9fbe754b3ba8963ceab0498e2a,

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

abstract = "Smoking is a common risk factor for many diseases. 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 dependence. 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). ",

keywords = "GENOME-WIDE ASSOCIATION, NICOTINIC ACETYLCHOLINE-RECEPTORS, LUNG-CANCER, SUSCEPTIBILITY LOCUS, MOLECULAR-GENETICS, HEAVY SMOKING, ADULT TWINS, DEPENDENCE, GENES, SNPS, 314 Health sciences",

author = "Thorgeirsson, {Thorgeir E.} and Gudbjartsson, {Daniel F.} and Surakka, {Ida Liisa} 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 Ripatti, {Samuli Olli} and Markus Perola and Johannes Kettunen and Huei-Yi Shen and Jaakko Kaprio and Leena Palotie and {ENGAGE Consortium}",

year = "2010",

doi = "10.1038/ng.573",

language = "English",

volume = "42",

pages = "448--453",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

}

Thorgeirsson, TE, Gudbjartsson, DF, Surakka, IL, 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, SO, Perola, M, Kettunen, J, Shen, H-Y , Kaprio, J, Palotie, L & ENGAGE Consortium 2010, 'Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior', Nature Genetics, vol. 42, s. 448-453. https://doi.org/10.1038/ng.573

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. / Thorgeirsson, Thorgeir E.; Gudbjartsson, Daniel F.; Surakka, Ida Liisa; Vink, Jacqueline M.; Amin, Najaf; Geller, Frank; Sulem, Patrick; Rafnar, Thorunn; Esko, Tonu; Walter, Stefan; Gieger, Christian; Rawal, Rajesh; Mangino, Massimo; Prokopenko, Inga; Maegi, Reedik; Keskitalo, Kaisu; Gudjonsdottir, Iris H.; Gretarsdottir, Solveig; Stefansson, Hreinn; Thompson, John R.; Aulchenko, Yurii S.; Nelis, Mari; Aben, Katja K.; den Heijer, Martin; Dirksen, Asger; Ashraf, Haseem; Soranzo, Nicole; Valdes, Ana M.; Steves, Claire; Uitterlinden, Andre G.; Hofman, Albert; Toenjes, Anke; Kovacs, Peter; Hottenga, Jouke Jan; Willemsen, Gonneke; Vogelzangs, Nicole; Doering, Angela; Dahmen, Norbert; Nitz, Barbara; Pergadia, Michele L.; Saez, Berta; De Diego, Veronica; Lezcano, Victoria; Garcia-Prats, Maria D.; Ripatti, Samuli Olli; Perola, Markus; Kettunen, Johannes; Shen, Huei-Yi ; Kaprio, Jaakko; Palotie, Leena; ENGAGE Consortium.

I: Nature Genetics, Vol. 42, 2010, s. 448-453.

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

TY - JOUR

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

AU - Thorgeirsson, Thorgeir E.

AU - Gudbjartsson, Daniel F.

AU - Surakka, Ida Liisa

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 Olli

AU - Perola, Markus

AU - Kettunen, Johannes

AU - Shen, Huei-Yi

AU - Kaprio, Jaakko

AU - Palotie, Leena

AU - ENGAGE Consortium

PY - 2010

Y1 - 2010

N2 - Smoking is a common risk factor for many diseases. 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 dependence. 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. 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 dependence. 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).

KW - GENOME-WIDE ASSOCIATION

KW - NICOTINIC ACETYLCHOLINE-RECEPTORS

KW - LUNG-CANCER

KW - SUSCEPTIBILITY LOCUS

KW - MOLECULAR-GENETICS

KW - HEAVY SMOKING

KW - ADULT TWINS

KW - DEPENDENCE

KW - GENES

KW - SNPS

KW - 314 Health sciences

U2 - 10.1038/ng.573

DO - 10.1038/ng.573

M3 - Article

VL - 42

SP - 448

EP - 453

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -