Bettinger JC1,4, Bowers MS1,2,4, Grotewiel M1,3, Kendler KS1,2,3, Miles MF1,3,4, Vladimirov VI1,2, Webb BT1,2, Riley BP1,2,3
1Virginia Commonwealth University Alcohol Research Center, Departments of 2Psychiatry, 3Human & Molecular Genetics and 4Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, USA
Despite the substantial challenges in identifying specific genes influencing alcohol dependence risk, alcohol-related phenotypes have some critical advantages for gene identification. Ethanol has been in the environment since the evolution of micro-organisms, and pathways and genes mediating ethanol response are highly conserved across species. To exploit this conservation, well-developed experimental approaches exist to test directly whether changes in candidate genes impact behavioral response to ethanol in a variety of model organisms, providing a critical means to demonstrate the functional role of candidate genes in ethanol response. In our recent genomewide association study (GWAS) of alcohol dependence, the genes nominated by our human case-control association study show highly correlated phenotypes related to sensitivity and acute functional tolerance. In invertebrate models, knockdown of COL6A3 and knockout of RYR3 orthologs reduce ethanol sensitivity while knockout of the KLF12 ortholog blocks development of acute functional tolerance. In mouse brain, COL6A3 expression is correlated with handling-induced convulsions and KLF12 expression is correlated with development of acute functional tolerance. This convergence across species adds substantial functional evidence that the loci associated with alcohol dependence in our study are directly involved in alcohol-related phenotypes relevant to dependence risk.