GENETICS OF VULNERABILITY TO NICOTINE ADDICTION

描述：（申请人摘要） 尽管吸烟对公众健康有重要意义， 对吸烟行为的强烈遗传影响（遗传性）的研究 估计高达70%），很少有专门设计的研究 以确定导致人类尼古丁成瘾风险的基因。 我们提出了一个大规模的基因定位研究，以确定特定的染色体 对风险至少有中等影响的位置或候选基因。 家庭将通过澳大利亚和芬兰成年人小组确定 双胞胎，以及澳大利亚双胞胎的配偶样本，他们被确定为 在早期的调查中有大量吸烟史。我们会进行 先证者的诊断电话采访和抽血，他们的全部 兄弟姐妹和父母，以确定至少有一个受影响的兄弟姐妹对 (ASP)与重度吸烟一致，并且至少有一位父母（目标 N=400个澳大利亚家庭，400个芬兰家庭，每个家庭约600个ASP）。 将使用这些家庭进行10 cM全基因组扫描， 用于鉴定候选染色体连锁分析的同胞配对方法 暗示联系的区域。传播不平衡检验方法将 用于测试候选基因对尼古丁依赖的影响（DSM-IV 尼古丁依赖标准和α-Fagerstrom尼古丁依赖性试验 得分>= 4），并且用于候选区域的精细映射。我们的研究将有 不仅具有来自三人组的候选等位基因（两个父母加上 尼古丁依赖的后代），但也与尼古丁依赖 非正常（“不受影响”）吸烟者。家庭中的可用性 控制将增加我们推断的可靠性。候选基因 测试包括CYP 2A 6，CYP 2D 6，多巴胺D1和D2受体基因。一 将在圣路易斯建立一个数据库（不含个人识别信息）， 包括基因型、诊断和其他相关信息，淋巴母细胞 将在圣路易斯建立细胞系储存库， 以及位于赫尔辛基的DNA储存库， 芬兰家庭，供分发给科学和技术委员会的合格成员。 社区

DESCRIPTION: (Applicant's Abstract) Despite the public health significance of smoking, and evidence from adult twin studies for a strong genetic influence on smoking behavior (heritability estimates as high as 70%), there has been little research designed specifically to identify genes that contribute to risk of addiction to nicotine in humans. We propose a large-scale gene mapping study to identify specific chromosomal locations or candidate genes that have at least a moderate effect on risk. Families will be ascertained through panels of adult Australian and Finnish twins, and a sample of spouses of Australian twins, who have been identified as having a history of heavy smoking in earlier surveys. We will conduct diagnostic telephone interviews and blood drawing on probands, their full siblings and parents, to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent (target N=400 Australian, 400 Finnish families with approximately 600 ASPs from each). A 10cM genome-wide scan will be conducted using these families, with affected sib pair methods of linkage analysis used to identify candidate chromosomal regions suggestive of linkage. A transmission disequilibrium test approach will be used to test for candidate gene effects on nicotine dependence (DSM-IV nicotine dependence criteria and a-Fagerstrom Test for Nicotine Dependence score >= 4), and for fine mapping of candidate regions. Our study will have the advantage of having not only candidate alleles from trios (two parents plus nicotine dependent offspring), but also sibships with both nicotine dependent and non-regular ("unaffected") smokers. The availability of these within family controls will increase the robustness of our inferences. Candidate genes to be tested include CYP2A6, CYP2D6, and the dopamine D1 and D2 receptor genes. A database(without personal identifiers) will be established in St. Louis that includes genotype, diagnostic, and other pertinent information, a lymphoblast cell line repository will be established in St. Louis for cell lines obtained from Australian families; and a repository in Helsinki for DNA obtained from Finnish families, for distribution to qualified members of the scientific community.