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

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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.