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.
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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
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U01HG004438 NHGRI NIH HHS United States
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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
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