Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD

Saccone, Nancy L., Culverhouse, Robert C., Schwantes-An, Tae-Hwi, Cannon, Dale S., Chen, Xiangning, Cichon, Sven, Giegling, Ina, Han, Shizhong, Han, Younghun, Keskitalo-Vuokko, Kaisu, Kong, Xiangyang, Landi, Maria Teresa, Ma, Jennie Z., Short, Susan E., Stephens, Sarah H., Stevens, Victoria L., Sun, Lingwei, Wang, Yufei, Wenzlaff, Angela S., Aggen, Steven H., Breslau, Naomi, Broderick, Peter, Chatterjee, Nilanjan, Chen, Jingchun, Heath, Andrew C., Heliovaara, Markku, Hoft, Nicole R., Hunter, David J., Jensen, Majken K., Martin, Nicholas G., Montgomery, Grant W., Niu, Tianhua, Payne, Thomas J., Peltonen, Leena, Pergadia, Michele L., Rice, John P., Sherva, Richard, Spitz, Margaret R., Sun, Juzhong, Wang, Jen C., Weiss, Robert B., Weiss, Robert B., Wheeler, William, Witt, Stephanie H., Yang, Bao-Zhu, Caporaso, Neil E., Ehringer, Marissa A., Eisen, Tim, Gapstur, Susan M., Gelernter, Joel, Houlston, Richard, Kaprio, Jaakko, Kendler, Kenneth S., Kraft, Peter, Leppert, Mark F., Li, Ming D., Madden, Pamela A. F., Nothen, Markus M., Pillai, Sreekumar, Rietschel, Marcella, Rujescu, Dan, Schwartz, Ann, Amos, Christopher I. and Bierut, Laura J. (2010) Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD. PLoS Genetics, 6 8: 1-16. doi:10.1371/journal.pgen.1001053

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Author Saccone, Nancy L.
Culverhouse, Robert C.
Schwantes-An, Tae-Hwi
Cannon, Dale S.
Chen, Xiangning
Cichon, Sven
Giegling, Ina
Han, Shizhong
Han, Younghun
Keskitalo-Vuokko, Kaisu
Kong, Xiangyang
Landi, Maria Teresa
Ma, Jennie Z.
Short, Susan E.
Stephens, Sarah H.
Stevens, Victoria L.
Sun, Lingwei
Wang, Yufei
Wenzlaff, Angela S.
Aggen, Steven H.
Breslau, Naomi
Broderick, Peter
Chatterjee, Nilanjan
Chen, Jingchun
Heath, Andrew C.
Heliovaara, Markku
Hoft, Nicole R.
Hunter, David J.
Jensen, Majken K.
Martin, Nicholas G.
Montgomery, Grant W.
Niu, Tianhua
Payne, Thomas J.
Peltonen, Leena
Pergadia, Michele L.
Rice, John P.
Sherva, Richard
Spitz, Margaret R.
Sun, Juzhong
Wang, Jen C.
Weiss, Robert B.
Weiss, Robert B.
Wheeler, William
Witt, Stephanie H.
Yang, Bao-Zhu
Caporaso, Neil E.
Ehringer, Marissa A.
Eisen, Tim
Gapstur, Susan M.
Gelernter, Joel
Houlston, Richard
Kaprio, Jaakko
Kendler, Kenneth S.
Kraft, Peter
Leppert, Mark F.
Li, Ming D.
Madden, Pamela A. F.
Nothen, Markus M.
Pillai, Sreekumar
Rietschel, Marcella
Rujescu, Dan
Schwartz, Ann
Amos, Christopher I.
Bierut, Laura J.
Title Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2010-08-01
Year available 2010
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1001053
Open Access Status DOI
Volume 6
Issue 8
Start page 1
End page 16
Total pages 16
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
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.
Formatted 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.
Keyword Smoking Behaviour
Cancer
Smoking related diseases
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 DA026911
K25 GM69590
IRG-58-010-50
P01 CA089392
U01 HG04422-01
HHSN268200782096
P01-HL72903
SCO104960
P30ES007784
K01 AA015336
P01 HD31921
21356
HEALTH-F4-2007-201413
5P01DK070756
5R01HL035464
01GS8152
NO1-CN-25522
NO1-CN-25515
NO1-CN-25512
NO1-CN-25513
NO1-CN-25516
NO1-CN-25511
NO1 CN-25524
NO1-CN-25518
NO1 CN-75022
NO1-CN-25476
NO1-CN-25404
U01 HG004446
U01HG004438
HHSN268200782096C
P01-HD31921
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
 
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Created: Thu, 31 Mar 2011, 01:24:46 EST by Debbie Banks on behalf of School of Medicine