Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
QIMR Home Page
GenEpi Home Page
Publications
Contacts
Research
Staff Index
Collaborators
Software Tools
Computing Resources
Studies
Search
GenEpi Intranet
PMID
20700436
TITLE
Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.
ABSTRACT
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.
DATE PUBLISHED
2010 Aug
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2010/02/23
accepted 2010/07/07
epublish 2010/08/05
entrez 2010/08/12 06:00
pubmed 2010/08/12 06:00
medline 2010/12/29 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Saccone NL Saccone Nancy L NL Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. nlims@genetics.wustl.edu
Culverhouse RC Culverhouse Robert C RC
Schwantes-An TH Schwantes-An Tae-Hwi TH
Cannon DS Cannon Dale S DS
Chen X Chen Xiangning X
Cichon S Cichon Sven S
Giegling I Giegling Ina I
Han S Han Shizhong S
Han Y Han Younghun Y
Keskitalo-Vuokko K Keskitalo-Vuokko Kaisu K
Kong X Kong Xiangyang X
Landi MT Landi Maria Teresa MT
Ma JZ Ma Jennie Z JZ
Short SE Short Susan E SE
Stephens SH Stephens Sarah H SH
Stevens VL Stevens Victoria L VL
Sun L Sun Lingwei L
Wang Y Wang Yufei Y
Wenzlaff AS Wenzlaff Angela S AS
Aggen SH Aggen Steven H SH
Breslau N Breslau Naomi N
Broderick P Broderick Peter P
Chatterjee N Chatterjee Nilanjan N
Chen J Chen Jingchun J
Heath AC Heath Andrew C AC
Heliövaara M Heliövaara Markku M
Hoft NR Hoft Nicole R NR
Hunter DJ Hunter David J DJ
Jensen MK Jensen Majken K MK
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Niu T Niu Tianhua T
Payne TJ Payne Thomas J TJ
Peltonen L Peltonen Leena L
Pergadia ML Pergadia Michele L ML
Rice JP Rice John P JP
Sherva R Sherva Richard R
Spitz MR Spitz Margaret R MR
Sun J Sun Juzhong J
Wang JC Wang Jen C JC
Weiss RB Weiss Robert B RB
Wheeler W Wheeler William W
Witt SH Witt Stephanie H SH
Yang BZ Yang Bao-Zhu BZ
Caporaso NE Caporaso Neil E NE
Ehringer MA Ehringer Marissa A MA
Eisen T Eisen Tim T
Gapstur SM Gapstur Susan M SM
Gelernter J Gelernter Joel J
Houlston R Houlston Richard R
Kaprio J Kaprio Jaakko J
Kendler KS Kendler Kenneth S KS
Kraft P Kraft Peter P
Leppert MF Leppert Mark F MF
Li MD Li Ming D MD
Madden PA Madden Pamela A F PA
Nöthen MM Nöthen Markus M MM
Pillai S Pillai Sreekumar S
Rietschel M Rietschel Marcella M
Rujescu D Rujescu Dan D
Schwartz A Schwartz Ann A
Amos CI Amos Christopher I CI
Bierut LJ Bierut Laura J LJ
INVESTIGATORS
JOURNAL
VOLUME: 6
ISSUE: 8
TITLE: PLoS genetics
ISOABBREVIATION: PLoS Genet.
YEAR: 2010
MONTH: Aug
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1553-7404
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Genet
COUNTRY: United States
ISSNLINKING: 1553-7390
NLMUNIQUEID: 101239074
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Comparative Study
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
Cites Neuropsychopharmacology. 2009 Feb;34(3):698-706 18704094
Cites Nat Genet. 2008 May;40(5):616-22 18385676
Cites Clin Cancer Res. 2009 Mar 1;15(5):1837-42 19223495
Cites Arch Gen Psychiatry. 2009 Mar;66(3):267-74 19255376
Cites PLoS Genet. 2009 Mar;5(3):e1000421 19300482
Cites Mol Psychiatry. 2009 May;14(5):501-10 18414406
Cites Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):453-66 19259974
Cites Nicotine Tob Res. 2009 Jul;11(7):785-96 19436041
Cites Biol Psychiatry. 2009 Jul 15;66(2):128-36 19217079
Cites Hum Mol Genet. 2009 Aug 15;18(16):3125-35 19443489
Cites Cancer Res. 2009 Aug 15;69(16):6633-41 19654303
Cites Cancer Res. 2009 Sep 1;69(17):6848-56 19706762
Cites Clin Cancer Res. 2009 Sep 1;15(17):5599; author reply 5599 19706810
Cites Hum Mol Genet. 2009 Oct 15;18(20):4007-12 19628476
Cites Am J Med Genet B Neuropsychiatr Genet. 2009 Oct 5;150B(7):926-33 19132693
Cites Am J Hum Genet. 2009 Nov;85(5):679-91 19836008
Cites Carcinogenesis. 2010 Feb;31(2):234-8 19955392
Cites PLoS Biol. 2010 Jan;8(1):e1000294 20126254
Cites J Thorac Oncol. 2009 Oct;4(10):1195-201 19641473
Cites Am J Med Genet B Neuropsychiatr Genet. 2010 Apr 5;153B(3):745-56 19859904
Cites Nat Genet. 2010 May;42(5):448-53 20418888
Cites Nat Genet. 2010 May;42(5):436-40 20418889
Cites Nat Genet. 2010 May;42(5):441-7 20418890
Cites Hum Mol Genet. 2010 Jul 1;19(13):2706-15 20418489
Cites Control Clin Trials. 2000 Dec;21(6 Suppl):349S-355S 11189687
Cites Prev Sci. 2000 Dec;1(4):173-81 11523746
Cites Cancer. 2002 May 1;94(9):2490-501 12015775
Cites Drug Alcohol Depend. 2003 Jun 5;70(3):295-307 12757967
Cites Cancer Epidemiol Biomarkers Prev. 2003 Aug;12(8):689-98 12917198
Cites Am J Cardiol. 1991 May 1;67(11):933-8 2018010
Cites Lancet. 1991 Aug 24;338(8765):464-8 1678444
Cites Pharmacogenomics J. 2008 Jun;8(3):209-19 17549066
Cites PLoS Genet. 2008 Jul;4(7):e1000125 18618000
Cites BMC Public Health. 2008;8:203 18538025
Cites Am J Psychiatry. 2008 Sep;165(9):1163-71 18519524
Cites Addiction. 2008 Sep;103(9):1544-52 18783506
Cites J Natl Cancer Inst. 2008 Sep 17;100(18):1326-30 18780872
Cites J Natl Cancer Inst. 2008 Nov 5;100(21):1552-6 18957677
Cites Cancer Res. 2008 Nov 15;68(22):9137-40 19010884
Cites Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3517-25 19029397
Cites JAMA. 1994 Nov 16;272(19):1497-505 7966841
Cites Bioinformatics. 2005 Jan 15;21(2):263-5 15297300
Cites Arch Gen Psychiatry. 2005 Sep;62(9):1042-51 16143736
Cites Nature. 2005 Oct 27;437(7063):1299-320 16255080
Cites Schizophr Res. 2006 Feb 28;82(2-3):213-23 16229988
Cites Hum Mol Genet. 2006 Dec 15;15(24):3498-507 17085484
Cites Hum Mol Genet. 2007 Jan 1;16(1):36-49 17135278
Cites Hum Mol Genet. 2007 Jan 1;16(1):24-35 17158188
Cites Twin Res Hum Genet. 2006 Dec;9(6):988-97 17254442
Cites Am J Hum Genet. 2007 May;80(5):856-66 17436240
Cites Nat Genet. 2007 Jul;39(7):870-4 17529973
Cites Am J Hum Genet. 2007 Sep;81(3):559-75 17701901
Cites PLoS One. 2008;3(1):e1395 18167554
Cites Kidney Int. 2008 Feb;73(4):489-96 18059457
Cites Mol Psychiatry. 2008 Apr;13(4):368-73 18227835
Cites Eur Respir J. 2008 Apr;31(4):869-73 18216052
Cites Nature. 2008 Apr 3;452(7187):633-7 18385738
Cites Nature. 2008 Apr 3;452(7187):638-42 18385739
Cites PLoS One. 2009;4(2):e4653 19247474
GRANTS
GRANTID AGENCY COUNTRY
5P01DK070756 NIDDK NIH HHS United States
5R01HL035464 NHLBI NIH HHS United States
5U01HG004399 NHGRI NIH HHS United States
AA11330 NIAAA NIH HHS United States
CA016672 NCI NIH HHS United States
CA121197 NCI NIH HHS United States
CA127219 NCI NIH HHS United States
CA133996 NCI NIH HHS United States
CA55769 NCI NIH HHS United States
DA-13783 NIDA NIH HHS United States
DA12849 NIDA NIH HHS United States
K01 AA015336 NIAAA NIH HHS United States
K01DA019498 NIDA NIH HHS United States
K01DA024758 NIDA NIH HHS United States
K02 DA021237 NIDA NIH HHS United States
K02 DA021237 NIDA NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
K08 DA019951 NIDA NIH HHS United States
K08 DA019951 NIDA NIH HHS United States
K08 DA019951-05 NIDA NIH HHS United States
K25 GM69590 NIGMS NIH HHS United States
N01 CN-25524 NCI NIH HHS United States
N01 CN-75022 NCI NIH HHS United States
N01 PC35145 NCI NIH HHS United States
N01-CN-25404 NCI NIH HHS United States
N01-CN-25476 NCI NIH HHS United States
N01-CN-25511 NCI NIH HHS United States
N01-CN-25512 NCI NIH HHS United States
N01-CN-25513 NCI NIH HHS United States
N01-CN-25514 NCI NIH HHS United States
N01-CN-25515 NCI NIH HHS United States
N01-CN-25516 NCI NIH HHS United States
N01-CN-25518 NCI NIH HHS United States
N01-CN-25522 NCI NIH HHS United States
P01 CA089392 NCI NIH HHS United States
P01 CA089392 NCI NIH HHS United States
P01 CA089392-08 NCI NIH HHS United States
P01 HD31921 NICHD NIH HHS United States
P01-HL72903 NHLBI NIH HHS United States
P01CA087969 NCI NIH HHS United States
P30 CA22453 NCI NIH HHS United States
P30ES007784 NIEHS NIH HHS United States
P60 DA011015 NIDA NIH HHS United States
R01 AA011949 NIAAA NIH HHS United States
R01 AA017889 NIAAA NIH HHS United States
R01 AA017889 NIAAA NIH HHS United States
R01 AA017889-01A1 NIAAA NIH HHS United States
R01 AA017889-02 NIAAA NIH HHS United States
R01 AA11998 NIAAA NIH HHS United States
R01 AA13320 NIAAA NIH HHS United States
R01 AA13321 NIAAA NIH HHS United States
R01 CA60691 NCI NIH HHS United States
R01 CA87895 NCI NIH HHS United States
R01 DA-12844 NIDA NIH HHS United States
R01 DA012845 NIDA NIH HHS United States
R01 DA021913 NIDA NIH HHS United States
R01 DA026911 NIDA NIH HHS United States
R01 DA12854 NIDA NIH HHS United States
R01 DA12890 NIDA NIH HHS United States
R03 DA023166 NIDA NIH HHS United States
R21 DA026901 NIDA NIH HHS United States
R21DA027070 NIDA NIH HHS United States
R24 HD041020 NICHD NIH HHS United States
R56 DA12854 NIDA NIH HHS United States
T32 AA007464 NIAAA NIH HHS United States
U01 HG004422 NHGRI NIH HHS United States
U01 HG004422-02 NHGRI NIH HHS United States
U01 HG004446 NHGRI NIH HHS United States
U01 HG04422-01 NHGRI NIH HHS United States
U01HG004438 NHGRI NIH HHS United States
U01HG04424 NHGRI NIH HHS United States
Intramural NIH HHS United States
Wellcome Trust United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Aged
Aged, 80 and over
Chromosomes, Human, Pair 15 genetics
European Continental Ancestry Group genetics
Female genetics
Humans genetics
Lung Neoplasms genetics
Male genetics
Middle Aged genetics
Nerve Tissue Proteins genetics
Polymorphism, Single Nucleotide genetics
Pulmonary Disease, Chronic Obstructive genetics
Receptors, Nicotinic genetics
Smoking genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 CHRNA5 protein, human
0 Nerve Tissue Proteins
0 Receptors, Nicotinic
OTHER ID's
OTHERID SOURCE
PMC2916847 NLM