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
Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International, Research Triangle Park, NC, USA.
deCODE Genetics/Amgen, Reykjavik, Iceland.
Transl Psychiatry. 2015 Oct 6;5(10):e651. doi: 10.1038/tp.2015.149.
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.
我们对尼古丁依赖进行了一项基于千人基因组计划推算的全基因组关联研究（GWAS）荟萃分析，尼古丁依赖由尼古丁依赖Fagerström测试定义，研究对象为来自5个欧洲血统样本的17074名曾经吸烟的人。我们在来自5个独立欧洲血统样本的7469名曾经吸烟的人中对新发现的变异进行了随访。我们在20号染色体q13区域的α-4烟碱型受体亚基（CHRNA4）基因中发现了全基因组显著关联：在所有样本中，rs2273500 - C的最低P值为8.0×10⁻⁹（频率 = 0.15；重度与轻度依赖相比的优势比 = 1.12，95%置信区间 = 1.08 - 1.17）。rs2273500 - C是一个剪接位点受体变异，导致一种预测会被无义介导的衰变靶向的CHRNA4转录本变体，它与生理正常的人脑中CHRNA4表达降低有关（最低P值 = 7.3×10⁻⁴）。重要的是，rs2273500 - C与肺癌风险增加有关（N = 28998，优势比 = 1.06，95%置信区间 = 1.00 - 1.12），可能是通过其对吸烟的影响，因为在调整吸烟因素后，rs2273500 - C与肺癌不再相关。使用包含不止单一“每日吸烟量”项目的吸烟行为标准，我们确定了一个具有重要调控特性的常见CHRNA4变异，它与尼古丁依赖及吸烟相关后果有关。
