Validation, independent replication and functional analysis of results  derived from three genome wide association (GWA) screens  for alcohol consumption in the general population

Coordinator:		PD Dr. Norbert Dahmen                                                                         Prof. Dr. H. Erich Wichmann
Institution:		Klinik für Psychiatrie und Psychotherapie der Universität Mainz                GSF Institute of Epidemiology
Homepage:		www-klinik.uni-mainz.de/psychiatrie

Relatively few studies have analyzed the genetic factors associated with quantitative alcohol consumption in the general population. Low to moderate drinking (e.g. one standard drink per day) is associated with reduced mortality and an above average general well being (Guebaly, 2007; Thun et al., 1997). High alcohol consumption is a prerequisite for alcohol dependency and a risk factor for disorders related to the amount of alcohol consumed such as liver fibrosis, pancreatitis and cardio-vascular disorders. Molecular genetic association and linkage studies have identified candidate loci for the trait high alcohol consumption (Bergen et al., 2003) and analyzed candidate genes (Carr et a., 2002, Kauhanen et al., 2000a, b). Results partly overlap with those from addiction studies confirming the complementarity of the two approaches. Epidemiological twin studies have shown that at least 25% of the genetic variance in alcohol consumption during the translation period between regular drinking and alcohol dependency can be explained by genetic factors (Liu et al., 2004). In addition, alcohol related quantitative traits are widely used in animal models (Hitzemann et al., 2004). In nonhuman primate models genetic factors contribute to a substantial portion to the variation in alcohol intake (Lorenz at al., 2006). Additive genetic effects as well as gene-environment interactions have been demonstrated (Barr et al 2004). Taken together, the systematic evaluation of genetic factors contributing to the amount of alcohol consumption in adequate population based exploratory and replication samples is not only a worthy goal in itself, but will also lead further salutogenic research as well as research into alcohol risk behavior.
We are using three genome wide association studies in general population samples (2544 individuals) studies that are underway (500 individuals) or already performed (2044 individuals) by the PIs and contributors to this subproject SP12 to identify novel candidate SNPs for the trait high alcohol consumption. Findings will be replicated in large, specifically characterized independent samples. We will then attempt to identify causal genetic variants by detailed molecular genetic studies as well as in vitro genotype phenotype assessment.