THE GENETICS OF NICOTINE DEPENDENCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 吸烟是一种非常普遍和有害的行为。每年，吸烟在全球范围内造成约300万人死亡，仅在美国就估计有43.5万人死亡。超过98%的烟草使用者是吸烟者。尽管少数吸烟者不每天吸烟，但大多数人每天吸烟，并在身体上依赖尼古丁，尼古丁是香烟烟雾的主要成瘾成分。像所有的物质依赖障碍一样，尼古丁依赖也有很大的可遗传成分。在过去的几十年里，许多大样本的双胞胎研究得出结论，遗传因素导致了成为经常吸烟的人的风险。多巴脱羧酶(DDC；又称L氨基酸脱羧酶；AADC)参与多巴胺、去甲肾上腺素和5-羟色胺的合成。由于中脑边缘多巴胺能系统参与包括尼古丁在内的许多药物的强化作用，DDC基因被认为是参与尼古丁依赖易感性(ND)发生的可能候选基因。我们在染色体10q22上发现了标记D10S42附近的一个区域，显示出显著的连锁。此外，我们还鉴定了三个符合至少一个ND连锁标准的区域：位于染色体9q31的标记D9S1825，位于标记D11S1993和D11S1344之间的11p11，以及位于标记D13S325和D13S788之间的13q13。经多项统计分析，具有显著或提示连锁的4个地区的多项ND指标均为阳性。综上所述，我们在10q22号染色体上发现了显著的连锁，并在第9、11和13号染色体上提示了AA样本中ND的主要遗传决定因素的连锁。最近，对9号染色体相连区域的关联研究有力地表明，酪氨酸激酶受体2基因(NTRK2)与尼古丁依赖有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cigarette smoking is a highly prevalent and harmful behavior. Annually, tobacco smoking is responsible for approximately three million deaths world-wide, with an estimated 435,000 deaths in the USA alone. More than 98% of tobacco users are cigarette smokers. Although a minority of tobacco smokers do not smoke daily, most do and are physically dependent on nicotine, the primary addictive component of cigarette smoke. Like all substance-dependence disorders, nicotine dependence has a substantial heritable component. Over the last few decades, many large-sample twin studies have concluded that genetics contributes to the risk of becoming a regualr smoker. DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). We found a region near marker D10S42 on chromosome 10q22 that showed a significant linkage. Additionally, we identified three regions that met the criteria for suggestive linkage to at least one ND measure: on chromosomes 9q31 at marker D9S1825, 11p11 between markers D11S1993 and D11S1344, and 13q13 between markers D13S325 adn D13S788. The four regions with significant or suggestive linkage were positive for multiple ND measures by multiple statistical methods. In summary, we found significant linkage on chromosome 10q22 and suggestive linkage on chromosomes 9, 11, and 13 for major genetic determinants of ND in an AA sample. Most recently, an association study of the linked region on chromosome 9 strongly suggests that the tyrosine kinase receptor 2 gene (NTRK2) is involved with nicotine dependence.