of animal studies is that ethanol metabolism and resulting differences in blood/brain alcohol concentrations can be and frequently are controlled for statistically, which would serve to mitigate detection of ADH or other ethanol metabolism genes as QTLs in many animal studies. That said, even when blood alcohol levels are allowed to vary freely in animal studies, they do not seem to correlate with behavioral sensitivity, suggesting that metabolic differences are not the most important determinants of genetic differences in sensitivity to ethanol (Crabbe et al, 2005). Finally, it must be kept in mind that, to date, most QTL mapping of alcohol-related phenotypes in mice has employed crosses derived from two strains. As a result, substantial existing genetic variation is not represented, leading to “blind spots” (Roberts et al., 2007) that limit comparison to human data. It remains to be determined whether or not this limitation contributes to the current lack of evidence for mouse alcohol response QTLs syntenic with the human chromosome 4 QTL. This issue will mitigate as future studies increasingly use the collaborative cross that includes wild-derived mouse strains to perform genome-wide QTL analyses, including chromosomal regions with little or no interrogation in BXD analyses.
