Detection of reciprocal quantitative trait loci for acute ethanol withdrawal and ethanol consumption in heterogeneous stock mice

Rationale: Previous studies have suggested that there is an inverse genetic relationship between ethanol consumption (two-bottle choice, continuous access) and ethanol withdrawal (e.g., Metten et al., Behav Brain Res 95:113-122, 1998a). Objectives: The current study used short-term selective breeding from heterogeneous stock (HS) animals to examine this relationship. The primary goal of the current study was to determine if reciprocal quantitative trait loci (QTLs) could be found in the selectively bred lines. The advantage of detecting QTLs in HS animals is that it is possible to extract a haplotype signature for the QTL, which in turn can be used to narrow the number of candidate genes generated from gene expression and sequence databases (see, e.g., Hitzemann et al., Mamm Genome 14:733-747, 2003). Results: Seven reciprocal QTLs were detected on chromosomes (Chr) 1 (two), 3, 6, 11, 16, and 17 that exceeded the nominal LOD threshold of 10; genetic drift, which occurs during selection, dramatically increases the LOD threshold. The proximal Chr 1 QTL was examined in some detail. The haplotype structure of the QTL was such that the LP/J allele was associated with low withdrawal and high consumption. The QTL appears to be located in a gene-poor region between 170 and 173 Mbp. Based on available sequence data, two plausible candidate genes emerge-Nos1ap and Atf6α. Conclusions: The data presented here confirm some aspects of the negative genetic relationship between acute ethanol withdrawal and ethanol consumption. The QTL data point to the potential involvement of NO signaling and/or the unfolded protein response.