Collagen IV (Joslyn et al., 2010) and VIII (Edenberg et al., 2010) genes were implicated in ethanol response and AD. COL6A3 is located in a QTL interval for alcohol withdrawal identified in the IASPSAD sample (Kuo et al., 2006). Although this signal did not replicate, our GWS association with potentially functional SNPs (GWAS3D results, Table 1) is supported by the reduced sensitivity after RNAi knockdown in C. elegans (Figure 4A), mapping to the Alcw5 QTL for HIC in mice and the strong correlation between expression and HIC in BXD lines (Figure 5A). COL6A3 encodes a component of the ECM, and there is mounting evidence (Lubbers et al., 2014) that multiple substances of abuse increase ECM remodeling, and that remodeling is required for the expected behavioral changes following exposure. Ethanol dose-dependently induces tissue plasminogen activator (tPA), required for ECM remodeling, which enhances ethanol reward (Bahi and Dreyer, 2012). Withdrawal seizures are reduced in tPA-deficient mice following chronic ethanol administration (Pawlak et al., 2005). Inhibition of proteolytic enzymes that degrade the ECM block escalated responding during acute withdrawal in dependent animals (Smith
