Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

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Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

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Title: Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence
Author: Hancock, D B; Reginsson, G W; Gaddis, N C; Chen, X; Saccone, N L; Lutz, S M; Qaiser, B; Sherva, R; Steinberg, S; Zink, F; Stacey, S N; Glasheen, C; Chen, J; Gu, F; Frederiksen, B N; Loukola, A; Gudbjartsson, D F; Brüske, I; Landi, M T; Bickeböller, H; Madden, P; Farrer, L; Kaprio, J; Kranzler, H R; Gelernter, J; Baker, T B; Kraft, P; Amos, C I; Caporaso, N E; Hokanson, J E; Bierut, L J; Thorgeirsson, T E; Johnson, E O; Stefansson, K

Note: Order does not necessarily reflect citation order of authors.

Citation: Hancock, D. B., G. W. Reginsson, N. C. Gaddis, X. Chen, N. L. Saccone, S. M. Lutz, B. Qaiser, et al. 2015. “Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.” Translational Psychiatry 5 (10): e651. doi:10.1038/tp.2015.149. http://dx.doi.org/10.1038/tp.2015.149.
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Abstract: We conducted a 1000 Genomes–imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10−9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08–1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10−4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00–1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single ‘cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
Published Version: doi:10.1038/tp.2015.149
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930126/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822338
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