impaired mitochondrial functioning and increased cellular toxicity; while over-expression of PPARGC1A alleviated the alcohol-induced cellular toxicity (Liu et al., 2014). In a Spanish Mediterranean sample, PPARGC1A was found to be associated with alcohol consumption (Frances et al., 2008). Animal studies have reported that chronic alcohol treatment increased liver PPARGC1A expression levels in rats and this was reversed with an anti-oxidant N-acetylcysteine (Caro et al., 2014). In addition, PPARGC1A was related to reduced alcohol intake in mice (Blednov et al., 2015). Finally, while not studying SRE-5 as an outcome, one association study found that interactions between variants in PPARGC1A and alcohol consumption were significantly associated with obesity in AA but not EA (Edwards et al., 2012). Thus, there is persuasive evidence for a potential ancestry specific effect of this gene on alcohol-related response. Other genes such as DHX15 (DEATH-box helicase 15), SOD3 (superoxide dismutase 3), CCDC149 (coiled-coil domain containing 149), and LGI2 (leucine rich repeat LDI family member 2) are also located within or near the chromosome 4 GWS region; however, none of them have previously been associated with alcohol dependence or related phenotypes.
