Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
Liu
Jason Z
JZ
Department of Statistics, University of Oxford, Oxford, UK.
Tozzi
Federica
F
Waterworth
Dawn M
DM
Pillai
Sreekumar G
SG
Muglia
Pierandrea
P
Middleton
Lefkos
L
Berrettini
Wade
W
Knouff
Christopher W
CW
Yuan
Xin
X
Waeber
Gérard
G
Vollenweider
Peter
P
Preisig
Martin
M
Wareham
Nicholas J
NJ
Zhao
Jing Hua
JH
Loos
Ruth J F
RJ
Barroso
Inês
I
Khaw
Kay-Tee
KT
Grundy
Scott
S
Barter
Philip
P
Mahley
Robert
R
Kesaniemi
Antero
A
McPherson
Ruth
R
Vincent
John B
JB
Strauss
John
J
Kennedy
James L
JL
Farmer
Anne
A
McGuffin
Peter
P
Day
Richard
R
Matthews
Keith
K
Bakke
Per
P
Gulsvik
Amund
A
Lucae
Susanne
S
Ising
Marcus
M
Brueckl
Tanja
T
Horstmann
Sonja
S
Wichmann
H-Erich
HE
Rawal
Rajesh
R
Dahmen
Norbert
N
Lamina
Claudia
C
Polasek
Ozren
O
Zgaga
Lina
L
Huffman
Jennifer
J
Campbell
Susan
S
Kooner
Jaspal
J
Chambers
John C
JC
Burnett
Mary Susan
MS
Devaney
Joseph M
JM
Pichard
Augusto D
AD
Kent
Kenneth M
KM
Satler
Lowell
L
Lindsay
Joseph M
JM
Waksman
Ron
R
Epstein
Stephen
S
Wilson
James F
JF
Wild
Sarah H
SH
Campbell
Harry
H
Vitart
Veronique
V
Reilly
Muredach P
MP
Li
Mingyao
M
Qu
Liming
L
Wilensky
Robert
R
Matthai
William
W
Hakonarson
Hakon H
HH
Rader
Daniel J
DJ
Franke
Andre
A
Wittig
Michael
M
Schäfer
Arne
A
Uda
Manuela
M
Terracciano
Antonio
A
Xiao
Xiangjun
X
Busonero
Fabio
F
Scheet
Paul
P
Schlessinger
David
D
St Clair
David
D
Rujescu
Dan
D
Abecasis
Gonçalo R
GR
Grabe
Hans Jörgen
HJ
Teumer
Alexander
A
Völzke
Henry
H
Petersmann
Astrid
A
John
Ulrich
U
Rudan
Igor
I
Hayward
Caroline
C
Wright
Alan F
AF
Kolcic
Ivana
I
Wright
Benjamin J
BJ
Thompson
John R
JR
Balmforth
Anthony J
AJ
Hall
Alistair S
AS
Samani
Nilesh J
NJ
Anderson
Carl A
CA
Ahmad
Tariq
T
Mathew
Christopher G
CG
Parkes
Miles
M
Satsangi
Jack
J
Caulfield
Mark
M
Munroe
Patricia B
PB
Farrall
Martin
M
Dominiczak
Anna
A
Worthington
Jane
J
Thomson
Wendy
W
Eyre
Steve
S
Barton
Anne
A
Mooser
Vincent
V
Francks
Clyde
C
Marchini
Jonathan
J
D000328:Adult; D000368:Aged; D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods; D002884:Chromosomes, Human, Pair 15; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000378:metabolism; D012907:Smoking
D005819:Genetic Markers; D011978:Receptors, Nicotinic