Genetic polymorphisms are associated with risk for AUD, as well as intermediate phenotypes at the molecular and behavioral level (e.g. ADH, ALDH, COMT, MAOB, HTR2B, FBKP5) (Ducci and Goldman, 2012). ADH and ALDH variants are some of the strongest genetic predictors of risk for developing AUD. ADH and ALDH are typically associated with decreased risk for alcohol dependence since variations result in increased toxic effects of acetaldehyde in the periphery (Edenberg and Foroud, 2006). Among the 39 differentially expressed genes identified in prefrontal cortex of human alcoholic subjects, one was from the ADH gene family, six were from the ALDH family, and four were from the cytochrome P450 family (Zhang et al., 2014a), suggesting coordinated disruption in alcohol metabolism. Also, an evolutionarily conserved GABA synthesis pathway in dopamine neurons is mediated by the aldehyde dehydrogenase, ALDH1A1, rather than the conventional enzymes, GAD65 and GAD67 (Kim et al., 2015). In midbrain dopamine neurons, GABA co-release is modulated by ethanol at blood alcohol concentrations observed during binge drinking, and decreased ALDH1A1 leads to enhanced alcohol intake and preference (Kim et al., 2015). Taken together, this implies that alcohol metabolism in brain is involved in reward-based behavior and addiction.
