Mapping murine loci for physical dependence on ethanol

Rationale: Alcoholism is associated with withdrawal (physical dependence), tolerance, or a maladaptive pattern of alcohol (ethanol) use. The well-documented difference in susceptibility to withdrawal after chronic ethanol exposure between the C57BL/6J and DBA/2J mouse strains provides an excellent starting point for dissecting genetic influences involved in physical dependence on ethanol. A quantitative trait locus (QTL) identifies the genomic location of a gene (or genes) affecting a trait of interest. Objectives: A genome-wide QTL mapping study was carried out to dissect the multifactorial nature of withdrawal after chronic ethanol exposure using 400 B6D2F(2) mice. Methods: To induce physical dependence, we used a standard paradigm in which mice were exposed to ethanol vapor for 72 h. The mice were then tested hourly for handling-induced convulsions (HICs) for 10 h and at hours 24 and 25. Ethanol withdrawal severity was first computed as the area under the 25-h HIC curve. Separate regression residuals were then calculated that corrected for individual differences in blood ethanol concentration at the time of withdrawal and baseline HIC severity (i.e. before ethanol exposure). Results: Statistical mapping yielded significant evidence (P<0.00005) for QTLs on chromosomes 19 and distal I that account for 45% of the genetic variance in ethanol withdrawal severity. The F-2 results also provide supporting evidence for a sex-limited QTL on chromosome 13, and QTLs on chromosomes 4 and proximal 1, which may account for an additional 38% of the genetic variance. The distal chromosome I QTL is a locus of major effect, accounting for 26% of the genetic variance. Experiments using two congenic strains more precisely mapped this QTL. Conclusions: The QTLs map near candidate genes involved in neurosteroid biosynthesis and signal transduction. Syntenic homology between human and mouse chromosomes suggests that genes related to physical dependence on ethanol may localize to human chromosome regions 10q23-q26, 1q21-q43, 2q11-q32, 5p15/5q14-q21, and 9p24-p22.