PuSH - Publication Server of Helmholtz Zentrum München: Genome-wide meta-analysis reveals common splice site acceptor variant in <em>CHRNA4</em> 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.* ; Brüske, I. ; Landi, M.T.* ; Bickeböller, H.* ; Madden, P.* ; Farrer, L.A.* ; 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.*

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

Transl. Psychiatry 5:e651 (2015)

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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.

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