Skip Navigation



Human Molecular Genetics Advance Access published online on November 29, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl438
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
16/1/36    most recent
ddl438v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Saccone, S. F.
Right arrow Articles by Bierut, L. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Saccone, S. F.
Right arrow Articles by Bierut, L. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press. All rights reserved

Cholinergic Nicotinic Receptor Genes Implicated in a Nicotine Dependence Association Study Targeting 348 Candidate Genes with 3,713 SNPs

Scott F. Sacconea,*,1, Anthony L. Hinrichsa,1, Nancy L. Saccone1, Gary A. Chase2, Karel Konvicka3, Pamela A.F. Madden1, Naomi Breslau4, Eric O. Johnson5, Dorothy Hatsukami6, Ovide Pomerleau7, Gary E. Swan8, Alison M. Goate1,9, Joni Rutter10, Sarah Bertelsen1, Louis Fox1, Douglas Fugman11, Nicholas G. Martin12, Grant W. Montgomery12, Jen C. Wang1, Dennis G. Ballinger3, John P. Rice1,9 and Laura Jean Bierut1

1 Department of Psychiatry, Washington University School of Medicine, Saint Louis, 63110, U.S.A. 2 Department of Health Evaluation Sciences, Penn State College of Medicine, Hershey, Pennsylvania, 17033, U.S.A. 3 Perlegen Sciences, Mountain View, California, 94043, U.S.A. 4 Department of Epidemiology, Michigan State University, East Lansing, Michigan, 48824, U.S.A. 5 Research Triangle Institute International, Research Triangle Park, North Carolina, 27709, U.S.A. 6 Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, 55454, U.S.A. 7 Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, 48109, U.S.A. 8 Center for Health Sciences, SRI International, Menlo Park, California, 94025, U.S.A. 9 Department of Genetics, Washington University School of Medicine, Saint Louis, 63110, U.S.A. 10 National Institute on Drug Abuse, Bethesda, Maryland, 20892, U.S.A. 11 Rutgers University Cell and DNA Repository, Rutgers University, Piscataway, New Jersey, 08854, U.S.A. 12 Queensland Institute of Medical Research, Queensland 4029, Australia

* Corresponding Author: Scott F. Saccone, Department of Psychiatry, Box 8134, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, Missouri 63110, Facsimile: 314-286-2577, Telephone: 314-286-2581, Electronic Mail: saccones{at}msnotes.wustl.edu

Received August 11, 2006; Revised November 13, 2006; Accepted November 13, 2006

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over three hundred candidate genes and analyzed 3,713 single nucleotide polymorphisms (SNPs) in 1,050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND)was used to assess dependence, where cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from a SNP representing CHRNB3, the ß3 nicotinic receptor subunit gene (p=9.4x10–5). Biologically, the most compelling evidence for a risk variant came from a nonsynonymous SNP in the {alpha}5 nicotinic receptor subunit gene CHRNA5 (p=6.4x10–4). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a two-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date, and has found novel risk loci which require confirmation by replication studies.

a These authors contributed equally to this manuscript


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cancer Res.Home page
Y. Liu, P. Liu, W. Wen, M. A. James, Y. Wang, J. E. Bailey-Wilson, C. I. Amos, S. M. Pinney, P. Yang, M. de Andrade, et al.
Haplotype and Cell Proliferation Analyses of Candidate Lung Cancer Susceptibility Genes on Chromosome 15q24-25.1
Cancer Res., October 1, 2009; 69(19): 7844 - 7850.
[Abstract] [Full Text] [PDF]

Home page
 Int J EpidemiolHome page
E. H Lips, V. Gaborieau, J. D McKay, A. Chabrier, R. J Hung, P. Boffetta, M. Hashibe, D. Zaridze, N. Szeszenia-Dabrowska, J. Lissowska, et al.
Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals
Int. J. Epidemiol., September 23, 2009; (2009) dyp288v1.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. L. Saccone, J. C. Wang, N. Breslau, E. O. Johnson, D. Hatsukami, S. F. Saccone, R. A. Grucza, L. Sun, W. Duan, J. Budde, et al.
The CHRNA5-CHRNA3-CHRNB4 Nicotinic Receptor Subunit Gene Cluster Affects Risk for Nicotine Dependence in African-Americans and in European-Americans
Cancer Res., September 1, 2009; 69(17): 6848 - 6856.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. C. Wang, C. Cruchaga, N. L. Saccone, S. Bertelsen, P. Liu, J. P. Budde, W. Duan, L. Fox, R. A. Grucza, J. Kern, et al.
Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5
Hum. Mol. Genet., August 15, 2009; 18(16): 3125 - 3135.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. M. Freathy, S. M. Ring, B. Shields, B. Galobardes, B. Knight, M. N. Weedon, G. D. Smith, T. M. Frayling, and A. T. Hattersley
A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy
Hum. Mol. Genet., August 1, 2009; 18(15): 2922 - 2927.
[Abstract] [Full Text] [PDF]

Home page
 AJPHHome page
M. C. Fiore and T. B. Baker
Stealing a March in the 21st Century: Accelerating Progress in the 100-Year War Against Tobacco Addiction in the United States
Am J Public Health, July 1, 2009; 99(7): 1170 - 1175.
[Abstract] [Full Text] [PDF]

Home page
 Nicotine Tob ResHome page
T. B. Baker, R. B. Weiss, D. Bolt, A. von Niederhausern, M. C. Fiore, D. M. Dunn, M. E. Piper, N. Matsunami, S. S. Smith, H. Coon, et al.
Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes
Nicotine Tob Res, July 1, 2009; 11(7): 785 - 796.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Wu, Z. Hu, D. Yu, L. Huang, G. Jin, J. Liang, H. Guo, W. Tan, M. Zhang, J. Qian, et al.
Genetic Variants on Chromosome 15q25 Associated with Lung Cancer Risk in Chinese Populations
Cancer Res., June 15, 2009; 69(12): 5065 - 5072.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
L. Paleari, E. Negri, A. Catassi, M. Cilli, D. Servent, R. D'Angelillo, A. Cesario, P. Russo, and M. Fini
Inhibition of Nonneuronal {alpha}7-Nicotinic Receptor for Lung Cancer Treatment
Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1141 - 1150.
[Abstract] [Full Text] [PDF]

Home page
 Arch Gen PsychiatryHome page
L. E. Hong, H. Gu, Y. Yang, T. J. Ross, B. J. Salmeron, B. Buchholz, G. K. Thaker, and E. A. Stein
Association of Nicotine Addiction and Nicotine's Actions With Separate Cingulate Cortex Functional Circuits
Arch Gen Psychiatry, April 1, 2009; 66(4): 431 - 441.
[Abstract] [Full Text] [PDF]

Home page
 Nicotine Tob ResHome page
R. A. Philibert, A. Todorov, A. Andersen, N. Hollenbeck, T. Gunter, A. Heath, and P. Madden
Examination of the Nicotine Dependence (NICSNP) Consortium findings in the Iowa adoption studies population
Nicotine Tob Res, March 23, 2009; (2009) ntn034v1.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. Quaak, C. P. van Schayck, A. M. Knaapen, and F. J. van Schooten
Genetic variation as a predictor of smoking cessation success. A promising preventive and intervention tool for chronic respiratory diseases?
Eur. Respir. J., March 1, 2009; 33(3): 468 - 480.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
F. S. Falvella, A. Galvan, E. Frullanti, M. Spinola, E. Calabro, A. Carbone, M. Incarbone, L. Santambrogio, U. Pastorino, and T. A. Dragani
Transcription Deregulation at the 15q25 Locus in Association with Lung Adenocarcinoma Risk
Clin. Cancer Res., March 1, 2009; 15(5): 1837 - 1842.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
K. Shiraishi, T. Kohno, H. Kunitoh, S.-i. Watanabe, K. Goto, Y. Nishiwaki, Y. Shimada, H. Hirose, I. Saito, A. Kuchiba, et al.
Contribution of nicotine acetylcholine receptor polymorphisms to lung cancer risk in a smoking-independent manner in the Japanese
Carcinogenesis, January 1, 2009; 30(1): 65 - 70.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
G. Joslyn, G. Brush, M. Robertson, T. L. Smith, J. Kalmijn, M. Schuckit, and R. L. White
Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans
PNAS, December 23, 2008; 105(51): 20368 - 20373.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
S. I. Rennard
Lessons from Multidisciplinary Cross-Fertilization: Chronic Obstructive Pulmonary Disease, Lung Cancer, and Heart Disease
Proceedings of the ATS, December 1, 2008; 5(8): 865 - 868.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
V. L. Stevens, L. J. Bierut, J. T. Talbot, J. C. Wang, J. Sun, A. L. Hinrichs, M. J. Thun, A. Goate, and E. E. Calle
Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking
Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3517 - 3525.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Le Marchand, K. S. Derby, S. E. Murphy, S. S. Hecht, D. Hatsukami, S. G. Carmella, M. Tiirikainen, and H. Wang
Smokers with the CHRNA Lung Cancer-Associated Variants Are Exposed to Higher Levels of Nicotine Equivalents and a Carcinogenic Tobacco-Specific Nitrosamine
Cancer Res., November 15, 2008; 68(22): 9137 - 9140.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
M. R. Spitz, C. I. Amos, Q. Dong, J. Lin, and X. Wu
The CHRNA5-A3 Region on Chromosome 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer
J Natl Cancer Inst, November 5, 2008; 100(21): 1552 - 1556.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
S. Wacholder, N. Chatterjee, and N. Caporaso
Intermediacy and Gene-Environment Interaction: The Example of CHRNA5-A3 Region, Smoking, Nicotine Dependence, and Lung Cancer
J Natl Cancer Inst, November 5, 2008; 100(21): 1488 - 1491.
[Full Text] [PDF]

Home page
 Eur Respir JHome page
R. P. Young, R. J. Hopkins, B. A. Hay, M. J. Epton, P. N. Black, and G. D. Gamble
Lung cancer gene associated with COPD: triple whammy or possible confounding effect?
Eur. Respir. J., November 1, 2008; 32(5): 1158 - 1164.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
P. Liu, H. G. Vikis, D. Wang, Y. Lu, Y. Wang, A. G. Schwartz, S. M. Pinney, P. Yang, M. de Andrade, G. M. Petersen, et al.
Familial Aggregation of Common Sequence Variants on 15q24-25.1 in Lung Cancer
J Natl Cancer Inst, September 17, 2008; 100(18): 1326 - 1330.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. V. Conti, W. Lee, D. Li, J. Liu, D. Van Den Berg, P. D. Thomas, A. W. Bergen, G. E. Swan, R. F. Tyndale, N. L. Benowitz, et al.
Nicotinic acetylcholine receptor {beta}2 subunit gene implicated in a systems-based candidate gene study of smoking cessation
Hum. Mol. Genet., September 15, 2008; 17(18): 2834 - 2848.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. PsychiatryHome page
W. Berrettini
Nicotine Addiction
Am J Psychiatry, September 1, 2008; 165(9): 1089 - 1092.
[Full Text] [PDF]

Home page
 Am. J. PsychiatryHome page
L. J. Bierut, J. A. Stitzel, J. C. Wang, A. L. Hinrichs, R. A. Grucza, X. Xuei, N. L. Saccone, S. F. Saccone, S. Bertelsen, L. Fox, et al.
Variants in Nicotinic Receptors and Risk for Nicotine Dependence
Am J Psychiatry, September 1, 2008; 165(9): 1163 - 1171.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. M. Kassam, P. M. Herman, N. M. Goodfellow, N. C. Alves, and E. K. Lambe
Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors
J. Neurosci., August 27, 2008; 28(35): 8756 - 8764.
[Abstract] [Full Text] [PDF]

Home page
 BioinformaticsHome page
S. F. Saccone, N. L. Saccone, G. E. Swan, P. A. F. Madden, A. M. Goate, J. P. Rice, and L. J. Bierut
Systematic biological prioritization after a genome-wide association study: an application to nicotine dependence
Bioinformatics, August 15, 2008; 24(16): 1805 - 1811.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. S. Zeiger, B. C. Haberstick, I. Schlaepfer, A. C. Collins, R. P. Corley, T. J. Crowley, J. K. Hewitt, C. J. Hopfer, J. Lessem, M. B. McQueen, et al.
The neuronal nicotinic receptor subunit genes (CHRNA6 and CHRNB3) are associated with subjective responses to tobacco
Hum. Mol. Genet., March 1, 2008; 17(5): 724 - 734.
[Abstract] [Full Text] [PDF]

Home page
 Am Soc Clin Oncol Ed BookHome page
G. E. Swan and C. N. Lessov-Schlaggar
The Genetics of Nicotine Addiction: Current Status and Future Directions
ASCO Educational Book, January 1, 2008; 2008(1): 70 - 73.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
G. Winterer, F. Musso, A. Konrad, G. Vucurevic, P. Stoeter, T. Sander, and J. Gallinat
Association of attentional network function with exon 5 variations of the CHRNA4 gene
Hum. Mol. Genet., September 15, 2007; 16(18): 2165 - 2174.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
R. McPherson, A. Pertsemlidis, N. Kavaslar, A. Stewart, R. Roberts, D. R. Cox, D. A. Hinds, L. A. Pennacchio, A. Tybjaerg-Hansen, A. R. Folsom, et al.
A Common Allele on Chromosome 9 Associated with Coronary Heart Disease
Science, June 8, 2007; 316(5830): 1488 - 1491.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.