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，但大多数变异在功能上是沉默的(非功能变异)。这些罕见的功能变异或多或少可以微妙地改变由这些基因编码的蛋白质的工作方式。例如，在表型上，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。功能基因变异很可能也决定了我们对物质依赖的易感性。如果人们正在寻找尼古丁依赖的遗传因素，神经性尼古丁乙酰胆碱受体(NAChRs)基因的功能变异可以被认为是主要的候选因素。本提案的主要目的是确定影响尼古丁依赖的发展、成瘾的严重程度以及成功和长期戒烟的机会的nAChR变体。我们的项目将包括系统地寻找功能性nAChR变体及其在患者中的分析。对于第一部分，将对nAChR基因的启动子、编码区和内含子区域以及375个非翻译区进行测序，并将获得的变体引入表达克隆。这些克隆将在不同的细胞类型中表达，并对其生物药理学特征进行详细分析。在与Schwerpenkt研究中心其他小组的密切合作下，随后将在具有不同尼古丁依赖内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。这种关联方法旨在确定在患者中被证明比在对照组中更频繁的变异，因此可能在尼古丁依赖中发挥因果作用。

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.