Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.
Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.
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DOI：
10.1038/mp.2013.72
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发表时间：
2014-05
影响因子：
11
通讯作者：
Kaprio, J.
中科院分区：
文献类型：
--
作者：
Loukola, A.;Wedenoja, J.;Keskitalo-Vuokko, K.;Broms, U.;Korhonen, T.;Ripatti, S.;Sarin, A-P;Pitkaniemi, J.;He, L.;Happola, A.;Heikkila, K.;Chou, Y-L;Pergadia, M. L.;Heath, A. C.;Montgomery, G. W.;Martin, N. G.;Madden, P. A. F.;Kaprio, J.
关键词：
吸烟是几种躯体疾病的主要危险因素，也是神经精神疾病的一个致病因素。吸烟行为和尼古丁依赖（ND）的全基因组关联（GWA）和候选基因研究揭示了太少的易感变异，无法解释估计的高遗传性。之前的大规模GWA研究对吸烟相关行为的相关性的表型定义非常有限，这可能阻碍了遗传效应的发现。我们对1114名成年双胞胎进行了全基因组关联分析，这些双胞胎来自基于人群的芬兰双胞胎队列研究。17个吸烟相关表型的可用性使我们能够全面描绘吸烟行为的维度，聚类为吸烟开始，吸烟量和ND的域。我们的研究结果突出了16p12.3上的一个位点，CLEC 19 A附近的几个SNP与吸烟量相关（P<1×10−6）。有趣的是，CLEC 19 A位于先前报道的注意缺陷多动障碍（ADHD）连锁位点附近，并且已经建立了ADHD和吸烟之间的明显联系。在DSM-IV ND诊断和ERBB 4（编码神经调节蛋白受体）2 q33上的几个SNP之间检测到有趣的初步关联（P<1×10−5）。ERBB 4和DSM-IV ND诊断之间的关联在一个独立的澳大利亚样本中被复制。有趣的是，在Turner等人的论文中，在小鼠慢性尼古丁暴露和戒断后，ErbB 4和神经调节蛋白3（Nrg 3）表达显著增加。Turner等人还在临床试验中检测到NRG 3 SNP与戒烟成功之间的关联。ERBB 4先前与精神分裂症相关;此外，它位于已建立的精神分裂症连锁基因座内，并且位于该样本中鉴定的吸烟者表型的连锁基因座内。作为一个结论，我们披露了新的初步证据ERBB 4参与ND，表明神经调节蛋白/ErbB信号通路参与成瘾，并提供了一个合理的联系精神分裂症和ND的高并发症。
Smoking is a major risk factor for several somatic diseases, and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Prior large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed genome-wide association analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked, and ND. Our results highlight a locus on 16p12.3, with several SNPs in the vicinity of CLEC19A showing association (P<1×10−6) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1×10−5) was detected between DSM-IV ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Interestingly, in the paper by Turner et al., significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice. Turner et al. also detected an association between NRG3 SNPs and smoking cessation success in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. As a conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.
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影响因子：
3.7
作者：
Caporaso N;Gu F;Chatterjee N;Sheng-Chih J;Yu K;Yeager M;Chen C;Jacobs K;Wheeler W;Landi MT;Ziegler RG;Hunter DJ;Chanock S;Hankinson S;Kraft P;Bergen AW
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影响因子：
2.7
作者：
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通讯作者：
Lloyd, KCK
影响因子：
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作者：
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