Analysis of novel nicotine dependence related candidate genes identified through a genome-wide association study

• Applicants: Privatdozent Dr. Norbert Dahmen; Professor Dr. Andreas Gal; Professor Dr. Dan Rujescu; Professor Dr. Heinz-Erich Wichmann
• Subject Area: Biological Psychiatry
• Term: from 2006 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 24716133

Aim of the study is to identify genes which influence nicotine-related behaviour. Towards this end, we will employ the results of a state of the art (Affymetrix 500k chip) genome wide association study of 1200 subjects from the KORA-sample that is currently being carried out by the GSF together with partners from the German National Genome Research Network (NGFN) and that will be completed within 2006. The close interchange with NGFN resources in combination with sophistically characterized study samples ensures that internationally competitive and truly novel genes will be evaluated. A stepwise procedure will be pursued: 1) In the 1200 subjects positive association results will be ranked according to strength of statistical association, accordance with existing candidate gene studies and overlap with data from linkage and rodent QTL studies. 2) In another independent sample from the KORA-study (n=2000) with refined clinical characterization of smoking status and strength of nicotine dependence (a questionnaire-based quantitative measure for nicotine dependence, Fagerstrom test), we will seek to selectively replicate our initial findings (400 most promising SNPs from the initial scan). 3) As of the acknowledged clinical heterogeneity of the phenotype nicotine dependence, we will finally test the remaining best 50 single nucleotide polymorphisms (SNPs) for association in further samples which capture aspects of this heterogeneity a) the Munich/Berlin sample (n=2800) in which smoking status in conjunction with neuropsychological and electrophysiological endophenotyping of the quantitative traits attentional capacity and processing speed has been conducted (phenotypes known to be strongly related to nicotine dependence) b) the Mainz sample (n=300) which is extensively clinically characterized. The five most strongly associated genes during step 3 will be followed up by fine mapping of the involved genes including haplotype analyses. This step-wise procedure will also serve as prototype strategy for future analyses since it is expected that during the second funding period of the priority program, a large sample of carefully phenotyped subjects will be available derived from the prospectively conducted multicenter study which will also be part of the priority program. This will allow to investigate potential associations with other nicotine dependence-related phenotypes. Also, functional characterization of the discovered genes and genetic variations is planned for the second funding period

• DFG Programme: Priority Programmes
• Subproject of: SPP 1226: Nicotine: Molecular and Physiological Effects in the Central Nervous System (CNS)
• Participating Person: Professor Dr. Georg Winterer