Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.
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).
Thorgeirsson
Thorgeir E
TE
[1] deCODE Genetics, Reykjavik, Iceland. [2] Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, California, USA.
Gudbjartsson
Daniel F
DF
Surakka
Ida
I
Vink
Jacqueline M
JM
Amin
Najaf
N
Geller
Frank
F
Sulem
Patrick
P
Rafnar
Thorunn
T
Esko
Tõnu
T
Walter
Stefan
S
Gieger
Christian
C
Rawal
Rajesh
R
Mangino
Massimo
M
Prokopenko
Inga
I
Mägi
Reedik
R
Keskitalo
Kaisu
K
Gudjonsdottir
Iris H
IH
Gretarsdottir
Solveig
S
Stefansson
Hreinn
H
Thompson
John R
JR
Aulchenko
Yurii S
YS
Nelis
Mari
M
Aben
Katja K
KK
den Heijer
Martin
M
Dirksen
Asger
A
Ashraf
Haseem
H
Soranzo
Nicole
N
Valdes
Ana M
AM
Steves
Claire
C
Uitterlinden
André G
AG
Hofman
Albert
A
Tönjes
Anke
A
Kovacs
Peter
P
Hottenga
Jouke Jan
JJ
Willemsen
Gonneke
G
Vogelzangs
Nicole
N
Döring
Angela
A
Dahmen
Norbert
N
Nitz
Barbara
B
Pergadia
Michele L
ML
Saez
Berta
B
De Diego
Veronica
V
Lezcano
Victoria
V
Garcia-Prats
Maria D
MD
Ripatti
Samuli
S
Perola
Markus
M
Kettunen
Johannes
J
Hartikainen
Anna-Liisa
AL
Pouta
Anneli
A
Laitinen
Jaana
J
Isohanni
Matti
M
Huei-Yi
Shen
S
Allen
Maxine
M
Krestyaninova
Maria
M
Hall
Alistair S
AS
Jones
Gregory T
GT
van Rij
Andre M
AM
Mueller
Thomas
T
Dieplinger
Benjamin
B
Haltmayer
Meinhard
M
Jonsson
Steinn
S
Matthiasson
Stefan E
SE
Oskarsson
Hogni
H
Tyrfingsson
Thorarinn
T
Kiemeney
Lambertus A
LA
Mayordomo
Jose I
JI
Lindholt
Jes S
JS
Pedersen
Jesper Holst
JH
Franklin
Wilbur A
WA
Wolf
Holly
H
Montgomery
Grant W
GW
Heath
Andrew C
AC
Martin
Nicholas G
NG
Madden
Pamela A F
PA
Giegling
Ina
I
Rujescu
Dan
D
Järvelin
Marjo-Riitta
MR
Salomaa
Veikko
V
Stumvoll
Michael
M
Spector
Tim D
TD
Wichmann
H-Erich
HE
Metspalu
Andres
A
Samani
Nilesh J
NJ
Penninx
Brenda W
BW
Oostra
Ben A
BA
Boomsma
Dorret I
DI
Tiemeier
Henning
H
van Duijn
Cornelia M
CM
Kaprio
Jaakko
J
Gulcher
Jeffrey R
JR
McCarthy
Mark I
MI
Peltonen
Leena
L
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics
C470410:CHRNA6 protein, human; C539371:CHRNB3 protein, human; D011978:Receptors, Nicotinic; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6