Genome-wide and candidate gene association study of cigarette smoking behaviors.
Genome-wide and candidate gene association study of cigarette smoking behaviors.
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DOI：
10.1371/journal.pone.0004653
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Bergen AW
中科院分区：
文献类型：
--
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
在两项全基因组关联研究（GWAS）的联合分析中，研究了常见遗传变异对一种或多种既定吸烟行为的贡献，这两项研究是癌症易感性遗传标记（CGEMS）项目的一部分，在前列腺、肺、结肠和卵巢（PLCO）试验的2，329名男性和护士健康研究（NHS）的2，282名女性中进行。我们分析了7个吸烟行为指标，4个连续指标（每天吸烟量[CPD]，开始吸烟时的年龄，吸烟持续时间和包年），3个二元指标（曾经吸烟与从不吸烟，每天吸烟≤10支与>10支[CPDBI]，当前吸烟与既往吸烟）。每个单核苷酸多态性（SNP）的关联性检验通过研究进行，并根据年龄、同居/婚姻状况、教育、地点和人口子结构的主要成分进行调整。在两项研究的任何联合分析中，没有一个SNP达到全基因组显著性（p<10−7）;我们观察到两到七个SNP，其中每一个p<10−5。在跨越烟碱受体CHRNA 3和CHRNA 5的chr15q25.1区域中，我们发现了多个与CPD相关的SNP（p<10−3），包括rs 1051730，它与尼古丁依赖，吸烟强度和肺癌风险相关。同时，我们从359个先验候选基因中选择了11，199个SNP，并进行了个体基因和基因组分析。在对每个基因进行多次测试后，我们确定了与每个吸烟行为相关的两到五个基因。除了CHRNA 3和CHRNA 5之外，MAOA还与CPDBI相关（基因水平p<5.4×10 - 5），我们的分析提供了chr15q25.1区域与吸烟强度之间关联的独立复制，以及与吸烟相关的多个其他基因座的数据行为值得进一步随访。
The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, ≤10 versus >10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10−7) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10−5 for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10−3), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4×10−5), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up.
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