Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.
Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.
Saccone
Nancy L
NL
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. nlims@genetics.wustl.edu
Culverhouse
Robert C
RC
Schwantes-An
Tae-Hwi
TH
Cannon
Dale S
DS
Chen
Xiangning
X
Cichon
Sven
S
Giegling
Ina
I
Han
Shizhong
S
Han
Younghun
Y
Keskitalo-Vuokko
Kaisu
K
Kong
Xiangyang
X
Landi
Maria Teresa
MT
Ma
Jennie Z
JZ
Short
Susan E
SE
Stephens
Sarah H
SH
Stevens
Victoria L
VL
Sun
Lingwei
L
Wang
Yufei
Y
Wenzlaff
Angela S
AS
Aggen
Steven H
SH
Breslau
Naomi
N
Broderick
Peter
P
Chatterjee
Nilanjan
N
Chen
Jingchun
J
Heath
Andrew C
AC
Heliövaara
Markku
M
Hoft
Nicole R
NR
Hunter
David J
DJ
Jensen
Majken K
MK
Martin
Nicholas G
NG
Montgomery
Grant W
GW
Niu
Tianhua
T
Payne
Thomas J
TJ
Peltonen
Leena
L
Pergadia
Michele L
ML
Rice
John P
JP
Sherva
Richard
R
Spitz
Margaret R
MR
Sun
Juzhong
J
Wang
Jen C
JC
Weiss
Robert B
RB
Wheeler
William
W
Witt
Stephanie H
SH
Yang
Bao-Zhu
BZ
Caporaso
Neil E
NE
Ehringer
Marissa A
MA
Eisen
Tim
T
Gapstur
Susan M
SM
Gelernter
Joel
J
Houlston
Richard
R
Kaprio
Jaakko
J
Kendler
Kenneth S
KS
Kraft
Peter
P
Leppert
Mark F
MF
Li
Ming D
MD
Madden
Pamela A F
PA
Nöthen
Markus M
MM
Pillai
Sreekumar
S
Rietschel
Marcella
M
Rujescu
Dan
D
Schwartz
Ann
A
Amos
Christopher I
CI
Bierut
Laura J
LJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics; D012907:Smoking / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic