GENETICS OF VULNERABILITY TO NICOTINE ADDICTION

描述：(申请人摘要) 尽管吸烟对公共健康具有重要意义，但来自成年双胞胎的证据 对吸烟行为有强烈遗传影响的研究(遗传力 估计高达70%)，几乎没有专门设计的研究 以确定导致人类尼古丁成瘾风险的基因。 我们建议进行大规模的基因定位研究，以确定特定的染色体。 至少对风险有适度影响的位置或候选基因。 家庭将通过成年澳大利亚人和芬兰人组成的小组进行确定 双胞胎，以及澳大利亚双胞胎的配偶样本，他们被确认为 在以前的调查中有重度吸烟史。我们将进行 诊断性电话采访和对先证者的抽血，他们的全部 兄弟姐妹和父母，以识别至少有一个受影响兄弟姐妹对的兄弟姐妹关系 (ASP)符合重度吸烟，且至少有一名在世父母(目标) N=400个澳大利亚家庭，400个芬兰家庭，每个家庭大约有600个ASP)。 将使用这些家系进行10 cM全基因组扫描，受影响的 SIB对连锁分析方法在候选染色体鉴定中的应用 暗示连锁的区域。传输不平衡测试方法将 用于测试尼古丁依赖的候选基因效应(DSM-IV 尼古丁依赖标准及尼古丁依赖的a-Fagerstrom检验 Score；=4)，并用于候选区域的精细映射。我们的研究将有 不仅拥有来自三人组的候选等位基因(两个亲本加上 尼古丁依赖的后代)，但也与尼古丁依赖的兄弟姐妹 以及不经常(“未受影响”的)吸烟者。这些在家庭中的可用性 控制将增加我们推论的稳健性。候选基因将是 检测的基因包括细胞色素P450 2A6、细胞色素P450 2 D6以及多巴胺D1和D2受体基因。一个 将在圣路易斯建立数据库(没有个人识别码)， 包括基因、诊断和其他相关信息，淋巴母细胞 将在圣路易斯为获得的细胞系建立细胞系储存库 来自澳大利亚家庭的DNA；以及赫尔辛基的一个DNA储存库 芬兰家庭，分发给合格的科学成员 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.