Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking

Citation

Stephens, Sarah H.; Hartz, Sarah M.; Hoft, Nicole R.; Saccone, Nancy L.; Corley, Robin C.; Hewitt, John K.; Hopfer, Christian J.; Breslau, Naomi; Coon, Hilary; & Chen, Xiangning, et al. (2013). Distinct Loci in the CHRNA5/CHRNA3/CHRNB4 Gene Cluster Are Associated With Onset of Regular Smoking. Genetic Epidemiology. vol. 37 (8) pp. 846-859 , PMCID: PMC3947535

Abstract

Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.

URL

http://dx.doi.org/10.1002/gepi.21760

Keyword(s)

CHRNA5

Reference Type

Journal Article

Journal Title

Genetic Epidemiology

Author(s)

Stephens, Sarah H.
Hartz, Sarah M.
Hoft, Nicole R.
Saccone, Nancy L.
Corley, Robin C.
Hewitt, John K.
Hopfer, Christian J.
Breslau, Naomi
Coon, Hilary
Chen, Xiangning
Ducci, Francesca
Dueker, Nicole
Franceschini, Nora
Frank, Josef
Han, Younghun
Hansel, Nadia N.
Jiang, Chenhui
Korhonen, Tellervo
Lind, Penelope A.
Liu, Jason
Lyytikäinen, Leo-Pekka
Michel, Martha
Shaffer, John R.
Short, Susan E.
Sun, Juzhong
Teumer, Alexander
Thompson, John R.
Vogelzangs, Nicole
Vink, Jacqueline M.
Wenzlaff, Angela
Wheeler, William
Yang, Bao-Zhu
Aggen, Steven H.
Balmforth, Anthony J.
Baumeister, Sebastian E.
Beaty, Terri H.
Benjamin, Daniel J.
Bergen, Andrew W.
Broms, Ulla
Cesarini, David
Chatterjee, Nilanjan
Chen, Jingchun
Cheng, Yu-Ching
Cichon, Sven
Couper, David
Cucca, Francesco
Dick, Danielle
Foroud, Tatiana
Furberg, Helena
Giegling, Ina
Gillespie, Nathan A.
Gu, Fangyi
Hall, Alistair S.
Hällfors, Jenni
Han, Shizhong
Hartmann, Annette M.
Heikkilä, Kauko
Hickie, Ian B.
Hottenga, Jouke Jan
Jousilahti, Pekka
Kaakinen, Marika
Kähönen, Mika
Koellinger, Philipp D.
Kittner, Stephen
Konte, Bettina
Landi, Maria-Teresa
Laatikainen, Tiina
Leppert, Mark
Levy, Steven M.
Mathias, Rasika A.
McNeil, Daniel W.
Medland, Sarah E.
Montgomery, Grant W.
Murray, Tanda
Nauck, Matthias
North, Kari E.
Paré, Peter D.
Pergadia, Michele
Ruczinski, Ingo
Salomaa, Veikko
Viikari, Jorma
Willemsen, Gonneke
Barnes, Kathleen C.
Boerwinkle, Eric
Boomsma, Dorret I.
Caporaso, Neil
Edenberg, Howard J.
Francks, Clyde
Gelernter, Joel
Grabe, Hans Jörgen
Hops, Hyman
Jarvelin, Marjo-Riitta
Johannesson, Magnus
Kendler, Kenneth S.
Lehtimäki, Terho
Magnusson, Patrik K. E.
Marazita, Mary L.
Marchini, Jonathan
Mitchell, Braxton D.
Nöthen, Markus M.
Penninx, Brenda W.
Raitakari, Olli
Rietschel, Marcella
Rujescu, Dan
Samani, Nilesh J.
Schwartz, Ann G.
Shete, Sanjay
Spitz, Margaret
Swan, Gary E.
Völzke, Henry
Veijola, Juha
Wei, Qingyi
Amos, Chris
Cannon, Dale S.
Grucza, Richard
Hatsukami, Dorothy
Heath, Andrew
Johnson, Eric O.
Kaprio, Jaakko
Madden, Pamela
Martin, Nicholas G.
Stevens, Victoria L.
Weiss, Robert B.
Kraft, Peter
Bierut, Laura J.
Ehringer, Marissa A.

Year Published

2013

Volume Number

37

Issue Number

8

Pages

846-859

ISSN/ISBN

1098-2272

DOI

10.1002/gepi.21760

PMCID

PMC3947535

NIHMSID

NIHMS538239

Reference ID

4681