The Genetics of Vulnerability to Nicotine Addictions

长期吸烟是癌症和过早死亡的主要可预防原因。这是 修订了美国研究人员之间的遗传流行病学合作的竞争性延续， 澳大利亚和芬兰，以确定影响重度吸烟和尼古丁依赖风险的基因。我们 已经从1200对符合重度吸烟的受影响同胞中获得了访谈数据和血液样本， 以及他们暴露在烟草中的兄弟姐妹，他们是通过澳大利亚和芬兰的双人小组招募的。QTL连锁 使用10 cM微卫星标记基因组扫描数据的分析发现，这两个基因都有很强的连锁信号 澳大利亚和芬兰的主要吸烟量(Hos)表型的亚样本，位于Chr 22 (联合单点LOD5.2，全基因组意义，p=0.003)。这种相互竞争的延续 寻求确定Chr 22上的一个或多个基因，利用现有的效率来促进HOS 数据和大量信息量大的样本，优势互补。这将通过(I)基因分型来实现 在现有的基因组扫描家族中，密度为1 cM的SNPs，以更好地定义我们的连锁高峰； 遗传关联研究，与高通量基因分型1500个SNPs在我们的主要连锁区 1000名无关的芬兰男性重度吸烟者(ATBC化学预防试验参与者吸烟40+ 每天吸烟)和1000名芬兰男性人口控制组(Health2000参与者)，以及1000名 无血缘关系的澳大利亚人，有规律、重度吸烟史，1000名澳大利亚人接触过烟草 控制组，1000名有规律但低吸烟史的澳大利亚控制组(50%女性 在每个澳大利亚系列中)；(3)在2000年第二次小组中确定的遗传联系的复制 ATBC男性重度吸烟者和另外2,000名男性人口控制，或在澳大利亚的大兄弟姐妹中 家系(针对澳大利亚特有的发现)；(Iv)对与SNPs相关的基因的额外SNPs进行基因分型 使用HOS，以确定与HOS关联最强的单倍型，并对其进行高低排序 尝试识别功能性SNPs的风险单倍型；以及(V)表征吸烟的贡献 任何基因的行为和相关的精神和其他物质使用障碍，使用 芬兰和澳大利亚家庭已经招募，以及额外的澳大利亚大兄弟姐妹家庭 形成一个一般的社区样本。

Long-term smoking is the leading preventable cause of cancers and of premature mortality. This is the revised competing continuation of a genetic epidemiologic collaboration among investigators in the U.S., Australia and Finland, to identify genes that influence risks for heavy smoking and nicotine dependence. We have obtained interview data and blood samples from 1200 affected sib pairs concordant for heavy smoking, and their tobacco-exposed siblings, recruited through the Australian and Finnish twin panels. QTL linkage analyses using 10cM microsatellite marker genome scan data have identified a strong linkage signal in both Australian and Finnish subsamples for our primary heaviness-of-smoking (HoS) phenotype, on Chr 22 (combined single-point LOD 5.2, genome-wide significance, p=0.003). This competing continuation seeks to identify the gene or genes on Chr 22 which are contributing to HoS using the efficiency of existing data and large informative samples with complimentary strengths. This will be achieved by (i) genotyping SNPs at 1cM density, in existing genome scan families, to better define our linkage peak; (ii) conducting a genetic association study, with high-throughput genotyping of 1500 SNPs within our primary linkage region in 1000 unrelated Finnish male heavy smokers (ATBC chemoprevention trial participants who smoked 40+ cigarettes per day) and 1000 Finnish male population controls (Health2000 participants), and in 1000 unrelated Australians with a history of regular, heavy cigarette smoking, 1000 Australian tobacco-exposed controls, and 1,000 Australian controls with a history of regular but low cigarette consumption (50% women in each Australian series); (iii) replication of genetic associations thus identified in a second panel of 2000 ATBC male heavy smokers and an additional 2,000 male population controls, or in Australian large sibship families (for Australian specific findings); (iv) genotyping additional SNPs for genes having SNPs associated with HoS, to identify haplotypes showing the strongest association for HoS, and sequencing high and low risk haplotypes to attempt to identify functional SNPs; and (v) characterizing the contributions to smoking behavior and correlated psychiatric and other substance use disorders of any genes thus identified, using the Finnish and Australian families already recruited, and additional Australian large sibship families that form a general community sample.