Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

TE Thorgeirsson; DF Gudbjartsson; I Surakka; JM Vink; Najaf Amin; F Geller; P Sulem; T Rafnar; T Esko; Stefan Walter; C Gieger; R Rawal; M Mangino; I Prokopenko; R Magi; K Keskitalo; IH Gudjonsdottir; S Gretarsdottir; H Stefansson; JR Thompson; YS Aulchenko; M Nelis; KK Aben; Mariska Heijer; A Dirksen; H Ashraf; N Soranzo; AM Valdes; C Steves; André Uitterlinden; Bert Hofman; A Tonjes; P Kovacs; JJ (Jouke Jan) Hottenga; G Willemsen; N Vogelzangs; A Doring; N Dahmen; B Nitz; ML Pergadia; B Saez; V De Diego; V Lezcano; MD Garcia-Prats; S Ripatti; M Perola; J Kettunen; AL Hartikainen; A Pouta; J Laitinen; M Isohanni; S Huei-Yi; M Allen; M Krestyaninova; AS Hall; GT Jones; AM van Rij; T Mueller; B Dieplinger; M Haltmayer; S Jonsson; SE Matthiasson; H Oskarsson; T Tyrfingsson; LA Kiemeney; JI Mayordomo; JS Lindholt; JH Pedersen; WA Franklin; H Wolf; GW Montgomery; AC Heath; NG Martin; PAF Madden; I Giegling; D Rujescu; MR Jarvelin; V Salomaa; M Stumvoll; TD Spector; HE Wichmann; A Metspalu; NJ Samani; BW Penninx; Ben Oostra; DI Boomsma; Henning Tiemeier; Cornelia Duijn; J Kaprio; JR Gulcher; MI McCarthy; L Peltonen; U Thorsteinsdottir; K Stefansson

doi:10.1038/ng.573

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

TE Thorgeirsson, DF Gudbjartsson, I Surakka, JM Vink, Najaf Amin, F Geller, P Sulem, T Rafnar, T Esko, Stefan Walter, C Gieger, R Rawal, M Mangino, I Prokopenko, R Magi, K Keskitalo, IH Gudjonsdottir, S Gretarsdottir, H Stefansson, JR ThompsonYS Aulchenko, M Nelis, KK Aben, Mariska Heijer, A Dirksen, H Ashraf, N Soranzo, AM Valdes, C Steves, André Uitterlinden, Bert Hofman, A Tonjes, P Kovacs, JJ (Jouke Jan) Hottenga, G Willemsen, N Vogelzangs, A Doring, N Dahmen, B Nitz, ML Pergadia, B Saez, V De Diego, V Lezcano, MD Garcia-Prats, S Ripatti, M Perola, J Kettunen, AL Hartikainen, A Pouta, J Laitinen, M Isohanni, S Huei-Yi, M Allen, M Krestyaninova, AS Hall, GT Jones, AM van Rij, T Mueller, B Dieplinger, M Haltmayer, S Jonsson, SE Matthiasson, H Oskarsson, T Tyrfingsson, LA Kiemeney, JI Mayordomo, JS Lindholt, JH Pedersen, WA Franklin, H Wolf, GW Montgomery, AC Heath, NG Martin, PAF Madden, I Giegling, D Rujescu, MR Jarvelin, V Salomaa, M Stumvoll, TD Spector, HE Wichmann, A Metspalu, NJ Samani, BW Penninx, Ben Oostra, DI Boomsma, Henning Tiemeier, Cornelia Duijn, J Kaprio, JR Gulcher, MI McCarthy, L Peltonen, U Thorsteinsdottir, K Stefansson

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

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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	Undefined/Unknown
Pages (from-to)	448-U135
Journal	Nature Genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.573
Publication status	Published - 2010

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Access to Document

10.1038/ng.573

http://hdl.handle.net/1765/19768

Cite this

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., Magi, R., Keskitalo, K., Gudjonsdottir, IH., 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

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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 = "TE Thorgeirsson and DF Gudbjartsson and I Surakka and JM Vink and Najaf Amin and F Geller and P Sulem and T Rafnar and T Esko and Stefan Walter and C Gieger and R Rawal and M Mangino and I Prokopenko and R Magi and K Keskitalo and IH Gudjonsdottir and S Gretarsdottir and H Stefansson and JR Thompson and YS Aulchenko and M Nelis and KK Aben and Mariska Heijer and A Dirksen and H Ashraf and N Soranzo and AM Valdes and C Steves and Andr{\'e} Uitterlinden and Bert Hofman and A Tonjes and P Kovacs and Hottenga, {JJ (Jouke Jan)} and G Willemsen and N Vogelzangs and A Doring and N Dahmen and B Nitz and ML Pergadia and B Saez and {De Diego}, V and V Lezcano and MD Garcia-Prats and S Ripatti and M Perola and J Kettunen and AL Hartikainen and A Pouta and J Laitinen and M Isohanni and S Huei-Yi and M Allen and M Krestyaninova and AS Hall and GT Jones and {van Rij}, AM and T Mueller and B Dieplinger and M Haltmayer and S Jonsson and SE Matthiasson and H Oskarsson and T Tyrfingsson and LA Kiemeney and JI Mayordomo and JS Lindholt and JH Pedersen and WA Franklin and H Wolf and GW Montgomery and AC Heath and NG Martin and PAF Madden and I Giegling and D Rujescu and MR Jarvelin and V Salomaa and M Stumvoll and TD Spector and HE Wichmann and A Metspalu and NJ Samani and BW Penninx and Ben Oostra and DI Boomsma and Henning Tiemeier and Cornelia Duijn and J Kaprio and JR Gulcher and MI McCarthy and L Peltonen and U Thorsteinsdottir and K Stefansson",

year = "2010",

doi = "10.1038/ng.573",

language = "Undefined/Unknown",

volume = "42",

pages = "448--U135",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

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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, Magi, R, Keskitalo, K, Gudjonsdottir, IH, Gretarsdottir, S, Stefansson, H, Thompson, JR, Aulchenko, YS, Nelis, M, Aben, KK, Heijer, M, Dirksen, A, Ashraf, H, Soranzo, N, Valdes, AM, Steves, C, Uitterlinden, A , Hofman, B, Tonjes, A, Kovacs, P, Hottenga, JJ, Willemsen, G, Vogelzangs, N, Doring, A, Dahmen, N, Nitz, B, Pergadia, ML, Saez, B, De Diego, V, Lezcano, V, Garcia-Prats, MD, Ripatti, S, Perola, M, Kettunen, J, Hartikainen, AL, 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, Jarvelin, MR, Salomaa, V, Stumvoll, M, Spector, TD, Wichmann, HE, Metspalu, A, Samani, NJ, Penninx, BW, Oostra, B, Boomsma, DI, Tiemeier, H, Duijn, C, 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, TE

AU - Gudbjartsson, DF

AU - Surakka, I

AU - Vink, JM

AU - Amin, Najaf

AU - Geller, F

AU - Sulem, P

AU - Rafnar, T

AU - Esko, T

AU - Walter, Stefan

AU - Gieger, C

AU - Rawal, R

AU - Mangino, M

AU - Prokopenko, I

AU - Magi, R

AU - Keskitalo, K

AU - Gudjonsdottir, IH

AU - Gretarsdottir, S

AU - Stefansson, H

AU - Thompson, JR

AU - Aulchenko, YS

AU - Nelis, M

AU - Aben, KK

AU - Heijer, Mariska

AU - Dirksen, A

AU - Ashraf, H

AU - Soranzo, N

AU - Valdes, AM

AU - Steves, C

AU - Uitterlinden, André

AU - Hofman, Bert

AU - Tonjes, A

AU - Kovacs, P

AU - Hottenga, JJ (Jouke Jan)

AU - Willemsen, G

AU - Vogelzangs, N

AU - Doring, A

AU - Dahmen, N

AU - Nitz, B

AU - Pergadia, ML

AU - Saez, B

AU - De Diego, V

AU - Lezcano, V

AU - Garcia-Prats, MD

AU - Ripatti, S

AU - Perola, M

AU - Kettunen, J

AU - Hartikainen, AL

AU - Pouta, A

AU - Laitinen, J

AU - Isohanni, M

AU - Huei-Yi, S

AU - Allen, M

AU - Krestyaninova, M

AU - Hall, AS

AU - Jones, GT

AU - van Rij, AM

AU - Mueller, T

AU - Dieplinger, B

AU - Haltmayer, M

AU - Jonsson, S

AU - Matthiasson, SE

AU - Oskarsson, H

AU - Tyrfingsson, T

AU - Kiemeney, LA

AU - Mayordomo, JI

AU - Lindholt, JS

AU - Pedersen, JH

AU - Franklin, WA

AU - Wolf, H

AU - Montgomery, GW

AU - Heath, AC

AU - Martin, NG

AU - Madden, PAF

AU - Giegling, I

AU - Rujescu, D

AU - Jarvelin, MR

AU - Salomaa, V

AU - Stumvoll, M

AU - Spector, TD

AU - Wichmann, HE

AU - Metspalu, A

AU - Samani, NJ

AU - Penninx, BW

AU - Oostra, Ben

AU - Boomsma, DI

AU - Tiemeier, Henning

AU - Duijn, Cornelia

AU - Kaprio, J

AU - Gulcher, JR

AU - McCarthy, MI

AU - Peltonen, L

AU - Thorsteinsdottir, U

AU - Stefansson, K

PY - 2010

Y1 - 2010

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

C2 - 20418888

SN - 1061-4036

VL - 42

SP - 448-U135

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -