Identification of functional nAChR variants and their role in nicotine addiction, schizophrenia and epilepsy

遗传变异是我们基因中常见的发现，但大多数变异是功能沉默的（非功能性变异）。这些罕见的功能变异或多或少会微妙地改变这些基因编码的蛋白质的工作方式。从表型上看，它们可以改变我们对药物的个体反应或我们对某些疾病的易感性。很可能功能性基因变异也决定了我们对物质依赖的倾向。如果人们正在寻找尼古丁依赖的遗传因素，神经元烟碱乙酰胆碱受体（nAChR）基因的功能变体可以被视为主要候选者。本提案的主要目的是鉴定影响尼古丁依赖发展、成瘾严重程度以及成功和长期戒烟机会的nAChR变体。我们的项目将包括功能性nAChR变体的系统搜索以及对患者的分析。第一部分对nAChR基因的启动子、编码区、内含子区和375位非翻译区进行测序，并将获得的变异体导入表达克隆。克隆将在不同的细胞类型中表达，并详细分析其生物药理学特征。与Schwerpunkt的其他小组密切合作，随后将在具有不同尼古丁依赖内在表型的患者以及精神分裂症患者的大样本中研究被证明具有功能的遗传变异。相关性方法旨在识别证明在患者中比对照组更常见的变异，因此可能在尼古丁依赖中起因果作用。

Genetic variants are a common finding in our genes, but most variants are functionally silent (non-functional variants). The rare functional variants can more or less subtly change the way the proteins encoded by those genes are working. Phenotypically they can, for example, alter our individual responses to drugs or our susceptibility for certain disorders. It is likely that functional gene variants also determine our liability for substance dependence. Functional variants in genes for neuronal nicotinic acetylcholine receptors (nAChRs) can be regarded as prime candidates if one is looking for genetic factors in nicotine dependence. The major aim of the present proposal is the identification of nAChR variants that influence the development of nicotine dependence, the severity of the addiction and the chances of successful and long-term smoking cessation. Our project will include the systematic search for functional nAChR variants as well as their analysis in patients. For the first part, the promoters, coding and intronic regions and 375 - untranslated regions of nAChR genes will be sequenced and the obtained variants introduced into expression clones. The clones will be expressed in different cell types and their biopharmacological profiles analysed in detail. In close cooperation with other groups in the Schwerpunkt genetic variants that prove to be functional will subsequently be studied in large samples of patients with different endophenotypes of nicotine dependence as well as in schizophrenic patients. The association approach aims to identify variants that prove to be more frequent in patients than in controls and are therefore likely to play a causal role in nicotine dependence.