GENETICS OF VULNERABILITY TO NICOTINE ADDICTION

尼古丁成瘾易感性的遗传学

• 批准号: 6024273
• 负责人: Pamela Ann Madden
• 金额: $ 114万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-25 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6024273
• 关键词: Australia; Internet; Scandinavian country; cell bank /registry; clinical research; family genetics; genetic mapping; genetic registry /resource /referral center; genetic susceptibility; human subject; mental disorders; molecular biology information system; nicotine; smoking; tobacco abuse; twin /multiplet

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.

描述：（申请人摘要） 尽管吸烟对公共卫生具有重要意义，并且来自成年双胞胎的证据 研究遗传对吸烟行为的强烈影响（遗传性 估计高达70%），专门设计的研究很少 识别导致人类尼古丁成瘾风险的基因。 我们提出了一项大规模基因图谱研究来识别特定的染色体 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，他们已被确定为 在早期调查中有大量吸烟史。我们将进行 对先证者进行诊断性电话访谈和抽血，他们的全部 兄弟姐妹和父母，以确定至少一对受影响的兄弟姐妹的兄弟姐妹身份 (ASP) 大量吸烟的协调表，以及至少一名在世父母（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）。 将使用这些家族进行 10cM 全基因组扫描，受影响的 用于鉴定候选染色体的连锁分析的同胞对方法 暗示联系的区域。传递不平衡测试方法将 用于测试候选基因对尼古丁依赖的影响（DSM-IV 尼古丁依赖标准和尼古丁依赖的 a-Fagerstrom 测试 分数> = 4），以及候选区域的精细映射。我们的研究将有 不仅具有来自三重奏的候选等位基因（两个父母加上 尼古丁依赖的后代），而且还有同时具有尼古丁依赖的同胞 和不经常（“不受影响”）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。候选基因为 测试的基因包括 CYP2A6、CYP2D6 以及多巴胺 D1 和 D2 受体基因。一个 数据库（不含个人标识符）将在圣路易斯建立 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，用于存放获得的细胞系 来自澳大利亚家庭；以及位于赫尔辛基的 DNA 储存库 芬兰家庭，分发给合格的科学成员 社区。