Etohc2^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Etohc2^DBA/2J
• Name: ethanol consumption 2; DBA/2J
• MGI ID: MGI:2155062
• QTL: Etohc2 Location: Chr2:85724269-85724407 bp Genetic Position: Chr2, cM position of peak correlated region/allele: 49.68 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: DBA/2J

Variant description

• Allele Type: QTL
• Inheritance: Dominant

Notes

Candidate Genes

J:99482

Several alcohol preference QTL map to proximal mouse Chromosome 2 including Alcp1 (47.5 cM), Ap2q (34 cM), Etohc1 (28 cM), and Etohc2 (50 cM). This study investigates Stxbp1 as a candidate gene for the chromosome 2 alcohol-associated locus.

Alcohol preferring inbred strain C57BL/6J and alcohol avoiding inbred strain DBA/2J differ at nucleotide 646 of the Stxbp1 sequence. G646A is a non-conservative change in the Stxbp1 coding sequence resulting in the absence of a turn/turn motif in the C57BL/6J allele.

Analysis of 23 BXD RI strains shows correlation of the Stxbp1 polymorphism to alcohol consumption, acute alcohol withdrawal severity, and alcohol-induced conditioned taste aversion. This observation was confirmed in 3 other experiments.

1) Stxbp1 genotype was established for 86 (C57BL/6J x DBA/2J)F2 animals. F2 homozygotes for C57BL/6J-derived Stxbp1 alleles display 2X increased alcohol consumption compared to heterozygotes, and 3.5X increased alcohol consumption compared to F2 DBA/2J homozygotes (P=0.001).The effect of the C57BL/6J-derived Stxbp1 allele appears to be additive.

2) Fourth generation phenotype-selection lines derived from C57BL/6J and DBA/2J progenitors were assessed for allele frequencies at Stxbp1. The low alcohol preferring selection line STDRLO showed significant enrichment for DBA/2J-derived Stxbp1 alleles compared to the high alcohol preferring selection line STDRHI (P<0.0001).

3) Stxbp1 genotype and alcohol consumption was analyzed in 15 inbred strains. Ten inbred strains carrying C57BL/6J-like Stxbp1 allele tend to consume more alcohol compared to the five inbred strains carrying DBA/2J-like Stxbp1 alleles. The difference in alcohol consumption did not reach statistical significant but supports the hypothesis that Stxbp1 is a candidate gene for alcohol preference traits.

J:110030

Candidate genes for alcohol traits were identified using gene expression analysis. Total brain RNA from 70-90 day old male mice were hybridized to DNA microarrays to detect expression differences between high and low alcohol preference selection lines (HAP and LAP, respectively) and high and low tolerance selection lines (HAFT and LAFT, respectively). All selection lines were derived from HS/Ibg and were between 19 to 24 generations of selective breeding. Candidate genes mapping to previously identified expression and behavior QTL intervals are described below. Candidate genes were also confirmed using strain distribution patterns from 30 BXD (C=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains.

Kif5c (32.5 cM) on mouse Chromosome 2 exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set. This gene maps near previously identified alcohol preference QTLs Alcp1 (47.5 cM), Ap2q (34 cM), Etohc1 (28 cM), Etohc2 (50 cM), and Alpq2 (45 cM).

Gstm1 (108.39 Mb) on mouse Chromosome 3 is more highly expressed in high alcohol preferring lines compared to low alcohol preferring lines. D3Ertd254e (aka LOC241944) at 19 cM exhibits differential expression between high and low acute functional tolerance strains in theBXD RI set. This gene maps near a previously identified locus at D3Pas1 (22.7 cM) associated with basal cAMP signaling.

Gnb1 at 79.4 cM (153.38 Mb) on mouse Chromosome 4 is more highly expressed in low alcohol preference lines compared to high alcohol preference lines (LOD=17.13). This gene maps near previously identified alcohol preference QTL Ap3q at 81 cM.

Evi5 (56 cM ) and Pdap1 on mouse Chromosome 5 exhibits differential expression between high and low acute functional tolerance strains in the BXDRI set. These genes map near a locus at D5Mit201 (44 cM) suggestively linked to alcohol preference.

On mouse Chromosome 9, 4930422I07Rik (88.99 Mb), D930028F11Rik (expressed sequence C130036J11; 48.5 Mb), and Mthfs (130.69 Mb) are more highly expressedin high alcohol preference lines compared to low alcohol preference lines (LOD=7.46, 9.5, and 7.16, respectively). Hyou1 (44.48 Mb) is more highly expressed in low alcohol preference lines compared to high alcohol preference lines (LOD=4.18). Hyou1 and D930028F11Rik map to the Alpq3 (alcohol preference QTL 3) interval (17 cM - 53 cM).

Flnb on mouse Chromosome 14 exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set. This gene maps near a previously identified QTL at D14Byu1 (o.5 cM) associated with basal and forskolin-induced cAMP signaling.

Brd2 at 18.5 cM (31.81 Mb) on mouse Chromosome 17 is more highly expressed in high alcohol preferring lines compared to low alcohol preferring lines (LOD=3.93).

Galnt1 (24.43 Mb) on mouse Chromosome 18 is more highly expressed in high alcohol preference lines compared to low alcohol preference lines (LOD=2.93).

Tbl1x (30.9 cM) on mouse Chromosome X exhibits differential expression between high and low acute functional tolerance strains in the BXD RI set.

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

J:52468

B6D2F2 (C57BL/6J x DBA/2J) and BXD Recombinant Inbred (RI) stains were analyzed to discover QTLs that affect ethanol consumption in mice. Regions on mouse Chromosome 2 and mouse Chromosome 9 showed significant associations with a preference for ethanol.Mouse Chromosome 2 marker D2Mit7 showed a significant association with the phenotype with a combined LOD score of 2.8. The Chromosome 2 QTL is designated as Etohc1. A second QTL was associated with D2Mit14a and designated as Etohc2 with a combined LOD score of 3.3.

J:20482

Linkage analysis was performed using female animals from 19 BXD/Ty (B=C57BL/6J; D=DBA/2J) recombinant inbred (RI) strains to identify loci associated with ethanol drinking phenotypes. Parental strain C57BL/6J exhibits increased consumption of unsweetened10% ethanol, saccharin sweetened 3% and 10% ethanol, and 0.2% saccharin solution compared to parental strain DBA/2J. C57BL/6J also exhibits increased preference for 10% ethanol and 0.2% saccharin over water compared to DBA/2J. QTL analysis identified several loci linked to sweetened and unsweetened ethanol consumption and saccharin consumption on several mouse Chromosomes.

Linkage to 3% ethanol consumption mapped to 14 cM on mouse Chromosome 1 near D1Mit1. Significant linkage to 3% ethanol consumption and saccharin consumption mapped to 34 cM near D1Mit5.1, Myl1, and D1Byu1. Significant linkage to sweetened 3% and 10% ethanol consumption mapped to 70 cM on mouse Chromosome 1 near Ren2. Linkage to sweetened 3% and 10% ethanol consumption mapped to 88 cM near D1Mit16.

Linkage to sweetened and unsweetened 10% ethanol consumption mapped to 49 cM on mouse Chromosome 2 near D2Mc2. This locus was verified in a subsequent study (Phillips et al. 1998; J:52468) is named Etohc2 (ethanol consumption 2).

Linkage to sweetened 3% and 10% ethanol consumption and saccharin consumption mapped to 24 cM on mouse Chromosome 3 near D3Mit5. Linkage to unsweetened 10% ethanol consumption and sweetened 3% and 10% ethanol consumption mapped to 72 cM - 75 cM near Pmv26, Iapls2-14, and Lamr1-rs4.

Linkage to unsweetened 3% and 10% ethanol consumption and sweetened 10% ethanol consumption mapped to 57 cM - 61 cM on mouse Chromosome 4 near Lck and Slc9h1 (formerly Nhe1). Aldh4a1 at 66 cM is a potential candidate gene. Linkage to saccharin consumption and sweetened 3% and 10% ethanol consumption mapped to 81 cM - 82 cM near Tas1r3 (formerly Sac), D4Bir1, and Tel4q.

Linkage to unsweetened 3% and 10% ethanol consumption mapped to 11 cM on mouse Chromosome 7 near Nudt19 (formerly D7Rp2). Linkage to unsweetened 3% and 10% ethanol consumption and sweetened 10% ethanol consumption mapped to 57 cM near Rasl4.

Linkage to unsweetened 3% ethanol consumption mapped to 23 cM near D8Bir2, and significant linkage to saccharin consumption mapped to 60 cM near Xmmv29. This locus maps near previously identified saccharin QTL Cons3 at 67 cM.

Linkage to unsweetened 10% ethanol consumption mapped to 27 cM - 28 cM on mouse Chromosome 9 near Drd2, Ncam1, and Xmmv2. This locus was verified in a subsequent study and is named Etohc3 (ethanol consumption 3). Animals with C57BL/6J-derived alleles at Etohc3 exhibit 2.5-fold increased ethanol consumption compared to animals with DBA/2J-derived alleles.

Linkage to saccharin consumption mapped to 40 cM - 48cM on mouse Chromosome 13 near D13Mit9, Rasa1, and Arsb (formerly As-1), and to 52 cM - 58 cM nearLth1 and D13Bir1.

Linkage to sweetened 10% ethanol consumption mapped to 37 on mouse Chromosome 15 near D15Mit3.

Linkage to unsweetened 3% ethanol consumption is associated with marker D0Tu8 (formerly D17Tu8). This marker may possibly reside on Chromosome 17 but a definitive location is unknown.

Linkage to saccharin consumption and sweetened 3% and 10% ethanol consumption mapped to 18 cM - 21 cM on mouseChromosome 18 near Iapls3-7, D18Mit14, and Nr3c1 (formerly Grl1).

References

• Original: J:52468 Phillips TJ, et al., Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption. Mamm Genome. 1998 Dec;9(12):936-41
• All: 2 reference(s)