Alcw2^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Alcw2^DBA/2J
• Name: alcohol withdrawal 2; DBA/2J
• MGI ID: MGI:2155928
• QTL: Alcw2 Location: Chr4:75859474-81361052 bp Genetic Position: Chr4, Syntenic

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased alcohol withdrawal risk compared to C57BL/6J. (J:40532)
• Inheritance: Not Specified

Notes

Candidate Genes

J:88800

Mpdz, a candidate gene for the alcohol withdrawal QTL Alcw2 on mouse Chromosome 4, was examined in this study. Short term selected lines were generated from a (C57BL/6J x DBA/2J)F2 intercross. Animals were selected for high alcohol withdrawal (HAW) or low alcohol withdrawal (LAW) phenotypes and bred for 4 generations. DBA/2J-derived alleles at Mpdz were enriched in the HAW population whereas C57BL/6J-derived alleles were enriched in the LAW population. This association is significant and exceeds that predicted from genetic drift.

The same short term selection strategy was used to generate high pentobarbital withdrawal (HPW) and low pentobarbital withdrawal (LPW) lines. Similarly, DBA/2J-derived alleles at Mpdz were enriched in the HPW population whereasC57BL/6J-derived alleles were enriched in the LPW population. This association is significant and exceeds that predicted from genetic drift.

J:98595

Microarray analysis was used to identify genes showing alcohol-induced differential expression between inbred strains C57BL/6J and DBA/2J. These genes were then correlated to alcohol-related QTLs to identify potential candidate genes. The experiment involved identifying genes expressed differentially in alcohol-induced and non-induced animals but the following list of candidate genes are only for alcohol-induced states.

On mouse Chromosome 4, several candidate genes were identified for Ap3q at 81 cM and Alcw2 at 40 cM. Candidate genes for Ap3q are Clic4, 2610510H01Rik, Park7, and Tnfrsf9 (75.5 cM). Candidate genes for Alcw2 are Mpdz (38.6 cM) and Nfib (38.6 cM).

J:98587

Microarray analysis was used to identify genes showing alcohol-induced differential expression between inbred strains C57BL/6J and DBA/2J. These genes were then correlated to 6 previously identified alcohol-related QTLs to identify potential candidate genes. Two different Affymetrix microarrays were used in the analysis. Brain expression data from parental strains and 56 (DBA/2J x C57BL/6J)F2 intercross animals were used for analysis.

On mouse Chromosome 4, the highest priority candidate genes identified for Alcw2 at 40 cM is Alad (30.6 cM). Other candidate genes with a ranking of modest priority were identified but are not listed here.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:40532

Authors localized quantitative trait loci involved with alcohol dependence/genetic predisposition to acute alcohol withdrawal in mice. BXD (C57BL/6J x DBA/2J) strains, B6D2 F2 animals, and HAW (high alcohol withdrawal) LAW (low alcohol withdrawal) animals was used to identify a QTL, Alcw2 (LOD = 5.6). This locus is in proximity to Tyrp1 on mouse Chromosome 4 approximately 40 cM from the centromere and accounts for about 6% of the total phenotypic variance in alcohol withdrawal between D2 and B6 strains (26% of the genetic variance).

J:36168

Linkage analysis was performed on 21 BXD (B=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains at a marker resolution of 1 cM to detect loci associated with alcohol withdrawal severity. Parental strain DBA/2J exhibits greater alcohol withdrawal severity compared to C57BL/6J. Loci contributing to high risk of withdrawal, Alcw1 and Alcw2, were detected at distal mouse Chromosome 1 with a LOD score of 5.8, and at 38 cM on mouse Chromosome 4 with a LOD score of 5.7 near the b locus (Tyrp1), respectively. DBA/2J-derived alleles confer increased alcohol withdrawal severity at Alcw1 and Alcw2. A locus contributing to protection from severe alcohol withdrawal mapped to 20 cM on mouse Chromosome 11 with a LOD score of 4.1 near D11Mit174. DBA/2J-derived alleles confer decreased alcohol withdrawal severity at Alcw3.

References

• Original: J:40532 Buck KJ, et al., Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J Neurosci. 1997 May 15;17(10):3946-55
• All: 6 reference(s)