Variants in nicotinic receptors and risk for nicotine dependence

Laura Jean Bierut, Jerry A. Stitzel, Jen C. Wang, Anthony L. Hinrichs, Richard A. Grucza, Xiaoling Xuei, Nancy L. Saccone, Scott F. Saccone, Sarah Bertelsen, Louis Fox, William J. Horton, Naomi Breslau, John Budde, C. Robert Cloninger, Danielle M. Dick, Tatiana Foroud, Dorothy Hatsukami, Victor Hesselbrock, Eric O. Johnson, John Kramer & 13 others Samuel Kuperman, Pamela A F Madden, Kevin Mayo, John Nurnberger, Ovide Pomerleau, Bernice Porjesz, Oliver Reyes, Marc Schuckit, Gary Swan, Jay A. Tischfield, Howard Edenberg, John P. Rice, Alison M. Goate

Research output: Contribution to journalArticle

410 Citations (Scopus)

Abstract

Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid var iant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

Original languageEnglish (US)
Pages (from-to)1163-1171
Number of pages9
JournalAmerican Journal of Psychiatry
Volume165
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

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Tobacco Use Disorder
Nicotinic Receptors
Smoking
Population
Amino Acids
Multigene Family
Cholinergic Receptors
Nicotine
Alleles
Phenotype

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Bierut, L. J., Stitzel, J. A., Wang, J. C., Hinrichs, A. L., Grucza, R. A., Xuei, X., ... Goate, A. M. (2008). Variants in nicotinic receptors and risk for nicotine dependence. American Journal of Psychiatry, 165(9), 1163-1171. https://doi.org/10.1176/appi.ajp.2008.07111711

Variants in nicotinic receptors and risk for nicotine dependence. / Bierut, Laura Jean; Stitzel, Jerry A.; Wang, Jen C.; Hinrichs, Anthony L.; Grucza, Richard A.; Xuei, Xiaoling; Saccone, Nancy L.; Saccone, Scott F.; Bertelsen, Sarah; Fox, Louis; Horton, William J.; Breslau, Naomi; Budde, John; Cloninger, C. Robert; Dick, Danielle M.; Foroud, Tatiana; Hatsukami, Dorothy; Hesselbrock, Victor; Johnson, Eric O.; Kramer, John; Kuperman, Samuel; Madden, Pamela A F; Mayo, Kevin; Nurnberger, John; Pomerleau, Ovide; Porjesz, Bernice; Reyes, Oliver; Schuckit, Marc; Swan, Gary; Tischfield, Jay A.; Edenberg, Howard; Rice, John P.; Goate, Alison M.

In: American Journal of Psychiatry, Vol. 165, No. 9, 09.2008, p. 1163-1171.

Research output: Contribution to journalArticle

Bierut, LJ, Stitzel, JA, Wang, JC, Hinrichs, AL, Grucza, RA, Xuei, X, Saccone, NL, Saccone, SF, Bertelsen, S, Fox, L, Horton, WJ, Breslau, N, Budde, J, Cloninger, CR, Dick, DM, Foroud, T, Hatsukami, D, Hesselbrock, V, Johnson, EO, Kramer, J, Kuperman, S, Madden, PAF, Mayo, K, Nurnberger, J, Pomerleau, O, Porjesz, B, Reyes, O, Schuckit, M, Swan, G, Tischfield, JA, Edenberg, H, Rice, JP & Goate, AM 2008, 'Variants in nicotinic receptors and risk for nicotine dependence', American Journal of Psychiatry, vol. 165, no. 9, pp. 1163-1171. https://doi.org/10.1176/appi.ajp.2008.07111711
Bierut, Laura Jean ; Stitzel, Jerry A. ; Wang, Jen C. ; Hinrichs, Anthony L. ; Grucza, Richard A. ; Xuei, Xiaoling ; Saccone, Nancy L. ; Saccone, Scott F. ; Bertelsen, Sarah ; Fox, Louis ; Horton, William J. ; Breslau, Naomi ; Budde, John ; Cloninger, C. Robert ; Dick, Danielle M. ; Foroud, Tatiana ; Hatsukami, Dorothy ; Hesselbrock, Victor ; Johnson, Eric O. ; Kramer, John ; Kuperman, Samuel ; Madden, Pamela A F ; Mayo, Kevin ; Nurnberger, John ; Pomerleau, Ovide ; Porjesz, Bernice ; Reyes, Oliver ; Schuckit, Marc ; Swan, Gary ; Tischfield, Jay A. ; Edenberg, Howard ; Rice, John P. ; Goate, Alison M. / Variants in nicotinic receptors and risk for nicotine dependence. In: American Journal of Psychiatry. 2008 ; Vol. 165, No. 9. pp. 1163-1171.
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abstract = "Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid var iant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0{\%} in African populations to 37{\%} in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.",
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AU - Bierut, Laura Jean

AU - Stitzel, Jerry A.

AU - Wang, Jen C.

AU - Hinrichs, Anthony L.

AU - Grucza, Richard A.

AU - Xuei, Xiaoling

AU - Saccone, Nancy L.

AU - Saccone, Scott F.

AU - Bertelsen, Sarah

AU - Fox, Louis

AU - Horton, William J.

AU - Breslau, Naomi

AU - Budde, John

AU - Cloninger, C. Robert

AU - Dick, Danielle M.

AU - Foroud, Tatiana

AU - Hatsukami, Dorothy

AU - Hesselbrock, Victor

AU - Johnson, Eric O.

AU - Kramer, John

AU - Kuperman, Samuel

AU - Madden, Pamela A F

AU - Mayo, Kevin

AU - Nurnberger, John

AU - Pomerleau, Ovide

AU - Porjesz, Bernice

AU - Reyes, Oliver

AU - Schuckit, Marc

AU - Swan, Gary

AU - Tischfield, Jay A.

AU - Edenberg, Howard

AU - Rice, John P.

AU - Goate, Alison M.

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N2 - Objective: A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the α5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. Method: Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid var iant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. Results: A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. Conclusions: This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.

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