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

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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 , Brueske , I , Landi , M T , Bickeboeller , 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 2015 , ' Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence ' , Translational Psychiatry , vol. 5 , 651 . https://doi.org/10.1038/tp.2015.149

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, Beenish; Sherva, R.; Steinberg, S.; Zink, F.; Stacey, S. N.; Glasheen, C.; Chen, J.; Gu, F.; Frederiksen, B. N.; Loukola, A.; Gudbjartsson, D. F.; Brueske, I.; Landi, M. T.; Bickeboeller, 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.
Contributor: University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2015-10-06
Language: eng
Number of pages: 11
Belongs to series: Translational Psychiatry
ISSN: 2158-3188
URI: http://hdl.handle.net/10138/162750
Abstract: We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerstrom 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 x 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 x 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.
Subject: LUNG-CANCER RISK
ACETYLCHOLINE-RECEPTORS
GENOTYPE IMPUTATION
SMOKING-BEHAVIOR
SUSCEPTIBILITY LOCUS
EUROPEAN-AMERICANS
CONTROLLED-TRIAL
CANDIDATE GENES
FAGERSTROM TEST
QUALITY-CONTROL
3124 Neurology and psychiatry
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