Azdm4^A/J
QTL Variant Detail

Summary

• QTL variant: Azdm4^A/J
• Name: Alzheimer's disease modifier 4; A/J
• MGI ID: MGI:3818005
• QTL: Azdm4 Location: unknown Genetic Position: Chr8, cM position of peak correlated region/allele: 15.33 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers decreased amyloid plaque number compared to C57BL/6J. (J:112037)
• Inheritance: Other (see notes)

Notes

Azdm4 is a modifier of Tg(PRNP-APPSweInd)8Dwst and exhibits additive inheritance.

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

J:112037

Linkage analysis was performed on 178 (A/J-Tg(PRNP-APPSweInd)8Dwst x C57BL/6J)F2 intercross animals to identify genetic modifiers of early onset Alzheimer's disease. The Tg(PRNP-APPSweInd)8Dwst transgene results in aggressive early onset Alzheimer's disease on a C57BL/6J background but is attenuated on an A/J background with longer survival time and lesser amyloid-beta deposition in brain plaques. Parental strain A/J-Tg(PRNP-APPSweInd)8Dwst has the following genetic makeup- 94% A/J, 5.5% FVB, and 0.5% C3H. Eighty polymorphic markers at a 20 cM resolution were used for the genome scan.

Azdm1 (Alzheimer's disease modifier 1) is a 49 Mb interval on mouse Chromosome 11 associated with several brain phenotypes. Significant linkage to plaque number (LOD=5.5), soluble amyloid-beta 40 (LOD=4.9), and soluble amyloid-beta 42 (LOD=7.2) mapped to 31.7 cM on mouse Chromosome 11 near D11Mit242. Significant linkage to amyloid plaque burden mapped to 36.1 cM at D11Mit4 (LOD=5.4). Azdm1 accounts for 13% of the plaque phenotype variance, 12% of the amyloid burden variance, 17% of the amyloid-beta 42 variance, and 12% of the amyloid-beta 40 variance. A/J-derived alleles at Azdm1 confer decreased plaque number and amyloid burden with additive inheritance, and decreased brain amyloid-beta 40 and 42 with co-dominant inheritance. There are 840 genes in the Azdm1 interval. Potential candidate genes include Scpep1, Abcc3, Rnf130, and Cias1. Previously identified QTL Pid3 (34 cM) maps near Azdm1. Linkage to insoluble amyloid-beta 42 peaked at 53.6 cM near D11Mit213 (LOD=4.9) and may represent a separate QTL. We tentatively designate this locus Azdm5 (Alzheimer's disease modifier 5).

Significant linkage to plaque number (LOD=8.1) and amyoloid burden (LOD=5.2) mapped to 66.7 cMon mouse Chromosome 4 near D4Mit251. This locus is named Azdm2 (Alzheimer's disease modifier 2) and explains 19% of the plaque number variance and 12% of the amyloid burden variance. A/J-derived alleles at Azdm2 confer decreased plaque number and amyloidburden with additive inheritance. The Azdm2 QTL interval spans 24 Mb and includes 350 genes. A potential candidate gene is Hspg2. (71.4 cM).

Significant linkage to plaque number (LOD=5) and amyloid burden (LOD=7.2) mapped to 33.9 cM on mouse Chromosome 9 near D9Mit336. This locus is named Azdm3 (Alzheimer's disease modifier 3) and explains 12% of the plaque number variance and 17% of the amyloid burden variance. A/J-derived alleles at Azdm3 confer decreased plaque number and amyloid burden with additive inheritance. The Azmd3 QTL interval spans 50 Mb. Previously identified QTL Appd1 (21 cM) maps near Azdm3.

Significant linkage to plaque number mapped to 8.7 cM on mouse Chromosome 8 near D8Mit223 (LOD=4.5). This locus is named Azdm4 (Alzheimer's diseasemodifier 4) and accounts for 13% of the variance. A/J-derived alleles at Azdm4 confer decreased plaque number with additive inheritance. The Azdm4 QTL intervals spans 9 Mb and contains 67 genes. Potential candidate genes include Wrn (20 cM) and Atp7b (10cM).

Suggestive linkage to serum amyloid-beta 40 mapped to mouse Chromosome 1 at D1Mit102 (75.4 cM, LOD=3.6), D1Mit159 (82 cM, LOD=3.4), and D1Mit291 (103 cM, LOD=3). Suggestive linkage to serum amyloid-beta 40 and 42 mapped to mouse Chromosome 6 at D6Mit209(21.9 cM, LOD=3.3 and 2.9, respectively). Suggestive linkage to serum amyloid-beta 42 mapped to mouse Chromosome 6 at D6Mit188 (21.9 cM, LOD=3.2).

References

• Original: J:112037 Sebastiani G, et al., Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice. Hum Mol Genet. 2006 Aug 1;15(15):2313-23
• All: 1 reference(s)