Multiple genes are located in the chromosome 4 GWS region. One of them is PPARGC1A (PPARG coactivator 1 alpha). Among the 15 variants that have P-values < 0.01 in fine mapping (Table 3), 13 are in introns of PPARGC1A. This gene is broadly expressed in multiple tissues including liver and brain. The protein product of this gene interacts with cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). Studies have found that the expression of the protein product of PPARGC1A was altered in post-mortem brain tissue from alcohol dependent individuals (Blednov et al., 2015; Ponomarev, Wang, Zhang, Harris, & Mayfield, 2012). Chronic alcohol exposure has also been shown to dramatically reduce cellular cAMP levels via a pathway involving PPARGC1A (Avila et al., 2016). In cultured neuronal cells, Liu et al (2014) found that ethanol suppressed PPARGC1A expression, causing 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
