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

Nancy L. Saccone; Robert C. Culverhouse; Tae Hwi Schwantes-An; Dale S. Cannon; Xiangning Chen; Sven Cichon; Ina Giegling; Shizhong Han; Younghun Han; Kaisu Keskitalo-Vuokko; Xiangyang Kong; Maria Teresa Landi; Jennie Z. Ma; Susan E. Short; Sarah H. Stephens; Victoria L. Stevens; Lingwei Sun; Yufei Wang; Angela S. Wenzlaff; Steven H. Aggen; Naomi Breslau; Peter Broderick; Nilanjan Chatterjee; Jingchun Chen; Andrew C. Heath; Markku Heliövaara; Nicole R. Hoft; David J. Hunter; Majken K. Jensen; Nicholas G. Martin; Grant W. Montgomery; Tianhua Niu; Thomas J. Payne; Leena Peltonen; Michele L. Pergadia; John P. Rice; Richard Sherva; Margaret R. Spitz; Juzhong Sun; Jen C. Wang; Robert B. Weiss; William Wheeler; Stephanie H. Witt; Bao Zhu Yang; Neil E. Caporaso; Marissa A. Ehringer; Tim Eisen; Susan M. Gapstur; Joel Gelernter; Richard Houlston; Jaakko Kaprio; Kenneth S. Kendler; Peter Kraft; Mark F. Leppert; Ming D. Li; Pamela A.F. Madden; Markus M. Nöthen; Sreekumar Pillai; Marcella Rietschel; Dan Rujescu; Ann Schwartz; Christopher I. Amos; Laura J. Bierut

doi:10.1371/journal.pgen.1001053

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

Nancy L. Saccone, Robert C. Culverhouse, Tae Hwi Schwantes-An, Dale S. Cannon, Xiangning Chen, Sven Cichon, Ina Giegling, Shizhong Han, Younghun Han, Kaisu Keskitalo-Vuokko, Xiangyang Kong, Maria Teresa Landi, Jennie Z. Ma, Susan E. Short, Sarah H. Stephens, Victoria L. Stevens, Lingwei Sun, Yufei Wang, Angela S. Wenzlaff, Steven H. AggenNaomi Breslau, Peter Broderick, Nilanjan Chatterjee, Jingchun Chen, Andrew C. Heath, Markku Heliövaara, Nicole R. Hoft, David J. Hunter, Majken K. Jensen, Nicholas G. Martin, Grant W. Montgomery, Tianhua Niu, Thomas J. Payne, Leena Peltonen, Michele L. Pergadia, John P. Rice, Richard Sherva, Margaret R. Spitz, Juzhong Sun, Jen C. Wang, Robert B. Weiss, William Wheeler, Stephanie H. Witt, Bao Zhu Yang, Neil E. Caporaso, Marissa A. Ehringer, Tim Eisen, Susan M. Gapstur, Joel Gelernter, Richard Houlston, Jaakko Kaprio, Kenneth S. Kendler, Peter Kraft, Mark F. Leppert, Ming D. Li, Pamela A.F. Madden, Markus M. Nöthen, Sreekumar Pillai, Marcella Rietschel, Dan Rujescu, Ann Schwartz, Christopher I. Amos, Laura J. Bierut

Research output: Contribution to journal › Article › peer-review

311 Scopus citations

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 metaanalysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-perday, 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-perday, 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.

Original language	English
Journal	PLoS Genetics
Volume	6
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1001053
State	Published - Aug 2010
Externally published	Yes

Access to Document

10.1371/journal.pgen.1001053

Cite this

Saccone, N. L., Culverhouse, R. C., Schwantes-An, T. H., Cannon, D. S., Chen, X., Cichon, S., Giegling, I., Han, S., Han, Y., Keskitalo-Vuokko, K., Kong, X., Landi, M. T., Ma, J. Z., Short, S. E., Stephens, S. H., Stevens, V. L., Sun, L., Wang, Y., Wenzlaff, A. S., ... Bierut, L. 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). https://doi.org/10.1371/journal.pgen.1001053

@article{199754c7de3c4f7eba6481229181e179,

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 metaanalysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-perday, 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-perday, 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.",

author = "Saccone, {Nancy L.} and Culverhouse, {Robert C.} and Schwantes-An, {Tae Hwi} and Cannon, {Dale S.} and Xiangning Chen and Sven Cichon and Ina Giegling and Shizhong Han and Younghun Han and Kaisu Keskitalo-Vuokko and Xiangyang Kong and Landi, {Maria Teresa} and Ma, {Jennie Z.} and Short, {Susan E.} and Stephens, {Sarah H.} and Stevens, {Victoria L.} and Lingwei Sun and Yufei Wang and Wenzlaff, {Angela S.} and Aggen, {Steven H.} and Naomi Breslau and Peter Broderick and Nilanjan Chatterjee and Jingchun Chen and Heath, {Andrew C.} and Markku Heli{\"o}vaara and Hoft, {Nicole R.} and Hunter, {David J.} and Jensen, {Majken K.} and Martin, {Nicholas G.} and Montgomery, {Grant W.} and Tianhua Niu and Payne, {Thomas J.} and Leena Peltonen and Pergadia, {Michele L.} and Rice, {John P.} and Richard Sherva and Spitz, {Margaret R.} and Juzhong Sun and Wang, {Jen C.} and Weiss, {Robert B.} and William Wheeler and Witt, {Stephanie H.} and Yang, {Bao Zhu} and Caporaso, {Neil E.} and Ehringer, {Marissa A.} and Tim Eisen and Gapstur, {Susan M.} and Joel Gelernter and Richard Houlston and Jaakko Kaprio and Kendler, {Kenneth S.} and Peter Kraft and Leppert, {Mark F.} and Li, {Ming D.} and Madden, {Pamela A.F.} and N{\"o}then, {Markus M.} and Sreekumar Pillai and Marcella Rietschel and Dan Rujescu and Ann Schwartz and Amos, {Christopher I.} and Bierut, {Laura J.}",

note = "Funding Information: NLS is the spouse of S.F. Saccone, who is listed as an inventor on a patent, “Markers of Addiction”, covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB, JCW and JPR are listed as inventors on a patent, “Markers of Addiction,” covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB has served as a consultant to Pfizer in 2008. XK is a full time employee of GlaxoSmithKline. SP was a full time employee of GlaxoSmithKline. Current affiliation is with Hoffman-La Roche. JK has served as a consultant to Pfizer in 2008. MDL has served as a consultant to NIH, deCODE genetics, University of Pennsylvania, Reckitt Benckiser Pharmaceuticals, Pennsylvania Department of Health, and Informational Managements Consulting. Dr. Li also serves as a scientific advisor to ADial Pharmaceuticals. TJP receives compensation from the University of Mississippi Medical Center; part of his salary has been supported by grants from NIDA, NCI, the University of Mississippi Health Care Cancer Institute, the Mississippi State Department of Health, Pfizer Inc., and GlaxoSmithKline. Funding Information: This analysis uses data from Add Health, a program project designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris, and funded by a grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. No direct support was received from grant P01-HD31921 for this analysis. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Persons interested in obtaining data files from Add Health should contact Add Health, Carolina Population Center, 123 W. Franklin Street, Chapel Hill, NC 27516-2524 ( [email protected] ).",

year = "2010",

month = aug,

doi = "10.1371/journal.pgen.1001053",

language = "English",

volume = "6",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "8",

}

Saccone, NL, Culverhouse, RC, Schwantes-An, TH, Cannon, DS, Chen, X, Cichon, S, Giegling, I, Han, S, Han, Y, Keskitalo-Vuokko, K, Kong, X, Landi, MT, Ma, JZ, Short, SE, Stephens, SH, Stevens, VL, Sun, L, Wang, Y, Wenzlaff, AS, Aggen, SH, Breslau, N, Broderick, P, Chatterjee, N, Chen, J, Heath, AC, Heliövaara, M, Hoft, NR, Hunter, DJ, Jensen, MK, Martin, NG, Montgomery, GW, Niu, T, Payne, TJ, Peltonen, L, Pergadia, ML, Rice, JP, Sherva, R, Spitz, MR, Sun, J, Wang, JC, Weiss, RB, Wheeler, W, Witt, SH, Yang, BZ, Caporaso, NE, Ehringer, MA, Eisen, T, Gapstur, SM, Gelernter, J, Houlston, R, Kaprio, J, Kendler, KS, Kraft, P, Leppert, MF, Li, MD, Madden, PAF, Nöthen, MM, Pillai, S, Rietschel, M, Rujescu, D, Schwartz, A, Amos, CI & Bierut, LJ 2010, 'Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD', PLoS Genetics, vol. 6, no. 8. https://doi.org/10.1371/journal.pgen.1001053

TY - JOUR

T1 - Multiple independent loci at chromosome 15q25.1 affect smoking quantity

T2 - A meta-analysis and comparison with lung cancer and COPD

AU - Saccone, Nancy L.

AU - Culverhouse, Robert C.

AU - Schwantes-An, Tae Hwi

AU - Cannon, Dale S.

AU - Chen, Xiangning

AU - Cichon, Sven

AU - Giegling, Ina

AU - Han, Shizhong

AU - Han, Younghun

AU - Keskitalo-Vuokko, Kaisu

AU - Kong, Xiangyang

AU - Landi, Maria Teresa

AU - Ma, Jennie Z.

AU - Short, Susan E.

AU - Stephens, Sarah H.

AU - Stevens, Victoria L.

AU - Sun, Lingwei

AU - Wang, Yufei

AU - Wenzlaff, Angela S.

AU - Aggen, Steven H.

AU - Breslau, Naomi

AU - Broderick, Peter

AU - Chatterjee, Nilanjan

AU - Chen, Jingchun

AU - Heath, Andrew C.

AU - Heliövaara, Markku

AU - Hoft, Nicole R.

AU - Hunter, David J.

AU - Jensen, Majken K.

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Niu, Tianhua

AU - Payne, Thomas J.

AU - Peltonen, Leena

AU - Pergadia, Michele L.

AU - Rice, John P.

AU - Sherva, Richard

AU - Spitz, Margaret R.

AU - Sun, Juzhong

AU - Wang, Jen C.

AU - Weiss, Robert B.

AU - Wheeler, William

AU - Witt, Stephanie H.

AU - Yang, Bao Zhu

AU - Caporaso, Neil E.

AU - Ehringer, Marissa A.

AU - Eisen, Tim

AU - Gapstur, Susan M.

AU - Gelernter, Joel

AU - Houlston, Richard

AU - Kaprio, Jaakko

AU - Kendler, Kenneth S.

AU - Kraft, Peter

AU - Leppert, Mark F.

AU - Li, Ming D.

AU - Madden, Pamela A.F.

AU - Nöthen, Markus M.

AU - Pillai, Sreekumar

AU - Rietschel, Marcella

AU - Rujescu, Dan

AU - Schwartz, Ann

AU - Amos, Christopher I.

AU - Bierut, Laura J.

N1 - Funding Information: NLS is the spouse of S.F. Saccone, who is listed as an inventor on a patent, “Markers of Addiction”, covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB, JCW and JPR are listed as inventors on a patent, “Markers of Addiction,” covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB has served as a consultant to Pfizer in 2008. XK is a full time employee of GlaxoSmithKline. SP was a full time employee of GlaxoSmithKline. Current affiliation is with Hoffman-La Roche. JK has served as a consultant to Pfizer in 2008. MDL has served as a consultant to NIH, deCODE genetics, University of Pennsylvania, Reckitt Benckiser Pharmaceuticals, Pennsylvania Department of Health, and Informational Managements Consulting. Dr. Li also serves as a scientific advisor to ADial Pharmaceuticals. TJP receives compensation from the University of Mississippi Medical Center; part of his salary has been supported by grants from NIDA, NCI, the University of Mississippi Health Care Cancer Institute, the Mississippi State Department of Health, Pfizer Inc., and GlaxoSmithKline. Funding Information: This analysis uses data from Add Health, a program project designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris, and funded by a grant P01-HD31921 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 23 other federal agencies and foundations. No direct support was received from grant P01-HD31921 for this analysis. Special acknowledgment is due Ronald R. Rindfuss and Barbara Entwisle for assistance in the original design. Persons interested in obtaining data files from Add Health should contact Add Health, Carolina Population Center, 123 W. Franklin Street, Chapel Hill, NC 27516-2524 ( [email protected] ).

PY - 2010/8

Y1 - 2010/8

N2 - 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 metaanalysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-perday, 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-perday, 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.

AB - 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 metaanalysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-perday, 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-perday, 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.

UR - http://www.scopus.com/inward/record.url?scp=77957366301&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1001053

DO - 10.1371/journal.pgen.1001053

M3 - Article

C2 - 20700436

AN - SCOPUS:77957366301

SN - 1553-7390

VL - 6

JO - PLoS Genetics

JF - PLoS Genetics

IS - 8

ER -

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

Abstract

Access to Document

Fingerprint

Cite this