GENETICS OF VULNERABILITY TO NICOTINE ADDICTION

尼古丁成瘾易感性的遗传学

• 批准号: 6378959
• 负责人: Pamela Ann Madden
• 金额: $ 113.23万
• 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/6378959
• 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：（申请人的摘要） 尽管吸烟的公共健康意义和成人双胞胎的证据 研究对吸烟行为产生强烈遗传影响（遗传力 估计高达70％），几乎没有专门设计的研究 确定有助于人类成瘾风险的基因。 我们提出了一项大规模基因映射研究，以识别特定的染色体 至少对风险影响中等影响的位置或候选基因。 将通过成人澳大利亚和芬兰的面板来确定家庭 双胞胎和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的历史。我们将进行 诊断性电话采访和绘画概率，他们的完整 兄弟姐妹和父母，识别至少一个受影响的SIB对的同胞 （ASP）与大量吸烟和至少一位亲生父母一致（目标 n = 400个澳大利亚人，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10厘米的全基因组扫描，并受到影响 SIB对链接分析方法用于识别候选染色体 暗示联系的地区。传输不平衡测试方法将 用于测试候选基因对尼古丁依赖性的影响（DSM-IV 尼古丁的依赖标准和A-Fagerstrom测试尼古丁依赖性 得分> = 4），用于候选区域的精细映射。我们的研究将有 不仅拥有三重奏的候选等位基因（两个父母Plus）的优势 尼古丁依赖的后代），但同时均与尼古丁依赖 和非规范（“未受影响”）吸烟者。这些在家庭中的可用性 控制措施将提高我们的推论的鲁棒性。候选基因为 测试包括CYP2A6，CYP2D6和多巴胺D1和D2受体基因。一个 数据库（没有个人标识符）将在圣路易斯建立 包括基因型，诊断和其他相关信息，淋巴细胞 细胞系存储库将在圣路易斯建立以获得的细胞系列 来自澳大利亚家庭；以及赫尔辛基的存储库，用于从 芬兰家庭，分配给科学的合格成员 社区。