Genes contributing to nicotine dependence in humans

导致人类尼古丁依赖的基因

• 批准号: 6869340
• 负责人: Kari Stefansson
• 金额: $ 115.86万
• 依托单位: DECODE GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869340
• 关键词: Scandinavian country; alleles; behavioral /social science research tag; clinical research; comorbidity; drug addiction; family genetics; genetic mapping; genetic screening; genetic susceptibility; genotype; high throughput technology; human subject; nicotine; pharmacogenetics; phenotype; polymerase chain reaction; smoking; substance abuse related behavior

DESCRIPTION (provided by applicant): Identification of genes whose variants contribute to nicotine dependence would have an enormous impact on the understanding and treatment for this common and intractable problem that represents one of the most important risk factors for numerous diseases. We propose to target for re-phenotyping a subset of the 30,000 Icelanders who have already answered smoking screening questionnaires. These 30,000 individuals have already been genotyped with a genome-wide linkage set of 1000 microsatellite markers and can be leveraged for this study. We propose to re-phenotype enough of this cohort to obtain at least 1000 individuals who have moderate to severe nicotine dependence according to a standard scale and who cluster into hundreds of extended families using our nationwide genealogy database. We will also collect at least two-thousand individuals who have smoked before but who did not become nicotine dependent to serve as non-dependent controls or first degree relatives of the affecteds. A large phenotype database will include data from Fagerstrom questionnaires and SSAGAII interviews to carefully define nicotine dependence and its co-morbidities. We will map loci for nicotine dependence through fully multipoint allele sharing linkage analysis that does not assume a particular inheritance model. Significant linkage peaks with high information content will be ultrafine-mapped with hundreds of markers to define the underlying LD structure. The regions will be assessed in a case-control analysis to look for significant haplotype association to nicotine dependence. Genes found in Iceland using this approach will be tested for their impact in outside populations already collected by our US co-investigators and advisory committee members. The extensive phenotype data on the nicotine dependent patients and relatives will be used in more careful genotype-phenotype correlations as a way to understand their role in nicotine dependence and its co-morbidities.

描述（由申请人提供）：鉴定其变异导致尼古丁依赖的基因将对理解和治疗这一常见且棘手的问题产生巨大影响，该问题是许多疾病最重要的风险因素之一。我们建议对已回答吸烟筛查问卷的 30,000 名冰岛人中的一部分进行重新表型分析。这 30,000 个人已经通过 1000 个微卫星标记的全基因组连锁集进行了基因分型，可用于本研究。我们建议对这个队列进行足够的重新表型分析，以获得至少 1000 名具有中度至重度尼古丁依赖的个体，这些个体根据标准量表，并使用我们的全国家谱数据库聚类成数百个大家庭。我们还将收集至少两千名以前吸烟但未产生尼古丁依赖的人作为非依赖对照或受影响者的一级亲属。大型表型数据库将包括来自 Fagerstrom 问卷和 SSAGAII 访谈的数据，以仔细定义尼古丁依赖及其并发症。我们将通过不假设特定遗传模型的完全多点等位基因共享连锁分析来绘制尼古丁依赖的基因座。具有高信息含量的重要连锁峰将使用数百个标记进行超细映射，以定义潜在的 LD 结构。这些区域将在病例对照分析中进行评估，以寻找与尼古丁依赖的显着单倍型关联。使用这种方法在冰岛发现的基因将被测试其对我们的美国联合研究人员和咨询委员会成员已经收集的外部人群的影响。关于尼古丁依赖患者和亲属的广泛表型数据将用于更仔细的基因型-表型相关性，作为了解他们在尼古丁依赖及其并发症中的作用的一种方式。