Lith21^NZB/BlNJ
QTL Variant Detail

Summary

• QTL variant: Lith21^NZB/BlNJ
• Name: lithogenic gene 21; NZB/BlNJ
• MGI ID: MGI:3577252
• QTL: Lith21 Location: Chr10:25525003-25525126 bp Genetic Position: Chr10, cM position of peak correlated region/allele: 12.51 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZB/BlNJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased gallstone weight compared to SM/J. (J:97646)
• Inheritance: Recessive

Notes

Candidate Genes

J:133501

SNP analysis, mRNA microarray analysis and protein expression difference analysis were used to narrow the QTL intervals of 9 previously identified QTLs for HDL cholesterol (Hdlq1, Hdlq20, Hdlq24), gallstone susceptibility (Lith17, Lith19, Lith21) and obesity (Obwq3, Obwq4, Obwq5). This methodology identified a manageable list of potential candidate genes for each QTL.

A panel of 130,000 SNPs for SM/J and NZB/BlNJ reduced the QTL intervals by 40%-72%. Liver mRNA analysis identified 10 genes differentially expressed between SM/J and NZB/BlNJ strains and this finding was confirmed using TaqMan RT-PCR assays. Mass spectrometry analysis of liver proteins identified 45 proteins displaying differential expression between SM/J andNZB/BlNJ.

On mouse Chromosome 1, Apoa2 (92.6 cM), Fh1, and Hsd11b1 were identified as potential candidate genes for Hdlq20 at 96 cM. Apoa2 was identified based on protein expression and SNP coding sequence differences. Apoa2 displays up-regulation in NZB/BlNJ liver proteins comparedto SM/J. Fh1 displays gene coding sequence differences and decreased protein expression in NZB/BlNJ livers compared to SM/J. Hsd11b1 was identified based on decreased protein expression in NZB/BlNJ.

On mouse Chromosome 5, Acads (65 cM) and Scarb1 (68 cM)were identified as potential candidate genes for Hdlq1 (70 cM) and Lith17 (60 cM). Acads was identified on the basis of decreased protein expression in NZB/BlNJ livers compared to SM/J, as well as coding sequence differences. Scarb1 displays coding regionsequence differences and decreased liver mRNA expression in NZB/BlNJ. Scarb1 is located more closely to Hdlq1 and decreased Scarb1 mRNA expression was observed for this QTL.

On mouse Chromosome 6, Pparg (52.7 cM), Rassf4 and Adipor2 (60.7 cM) were identified as potential candidate genes for Hdlq24 (66 cM) and Obwq3 (42 cM). Pparg displays coding sequences differences between NZB/BlNJ and SM/J while Rassf4 displays decreased liver mRNA expression in NZB/BlNJ animals. Adipor2 displays increased liver mRNAexpression in NZB/BlNJ and gene coding sequence differences. Ndufa9 was identified as a QTL for Hdlq24 on the basis of decreased liver protein expression in NZB/BlNJ and coding sequence differences.

On mouse Chromosome 8,Slc10a2 (2 cM) was identifiedasa potential candidate gene for Lith19 (0 cM) on the basis of increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

On mouse Chromosome 10, Ctgf (17 cM) was identified as a potential candidate gene for Lith21 (24 cM)on the basis of decreased liver mRNA expression in NZB/BlNJ animals compared to SM/J and gene coding sequences differences.

On mouse Chromosome 17, Pgc (30 cM) was identified as a potential candidate for Obwq4 (32 cM).Pgc displays coding sequence differences between NZB/BlNJand SM/J.

Atrnl1 was identified as a candidate for Obwq5 (52 cM) on chromosome 19. Atrnl1 displays increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

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

J:97646

Linkage analysis was performed on 489 (SM/J x NZB/BlNJ)F2 animals to identify QTLs associated with susceptibility to gallstone formation. Parental strain NZB/BlNJ is susceptible to gallstone development on a high fat diet whereas parental strain SM/J is resistant. Animals were placed on a high fat, high cholesterol diet for 18 weeks starting at 6-8 weeks of age. 154 SSLP markers were used for the genome scan.

Significant linkage to gallstone weight and gallstone presence mapped to mouse Chromosome 5 at 60 cM (Lith17) and 76 cM (Lith18). Lith17 is linked to D5Mit24 with LOD=3.4 for gallstone weight and LOD=5.4 for gallstone presence. The Lith17 95% confidence interval spans 40 cM - 65 cM. SM/J-derived alleles at Lith17 confer increased gallstone weight and incidence with an additive mode of inheritance. Lith17 locus shows overlap with a previously identified gallstone QTL named Lith13 (30 cM). Lith18 is linked to D8Mit284 with LOD=4.3 for gallstone weight and LOD=3.9 for gallstone presence. The 95% confidence interval of Lith18 spans 70 cM - 80 cM. SM/J-derived alleles at Lith18 confer increased gallstone weight and incidence with an additive mode of inheritance.

Lith19 mapped to 0 cM on mouse Chromosome 8 near D8Mit155 with LOD=5.1 for gallstone weight and LOD=5.3 for gallstone presence. The 95% confidence interval of Lith19 spans 0 cM - 8 cM. SM/J-derived alleles at Lith19 confer increased gallstone weight and incidence with a recessive mode of inheritance. A potential candidate gene for Lith19 is Slc10a2 at 2 cM.

Suggestive linkage to gallstone weight mapped to 44 cM on mouse Chromosome 9 near D9Mit73 (LOD=2.7). This locus is named Lith20 because it confirms a linkage detected in a previous cross. The 95% confidence interval of Lith20 spans 33 cM -50 cM. SM/J-derived alleles at Lith20 confer increased gallstone weight with a recessive mode of inheritance. Lith5 colocalizes with Lith20 and is thought to be the same QTL.

Suggestive linkage to gallstone presence mapped to 24 cM on mouse Chromosome 10 with LOD=2.9 at D10Mit214. This locus named Lith21 because it confirms a linkage detected in a previous cross. The 95% confidence interval of Lith21 spans 10 cM - 40 cM. NZB/BlNJ-derived alleles confer increased gallstone incidence with a recessive mode of inheritance.

An interacting locus named Lith22 was detected at 65 cM on mouse Chromosome 7 near D7Mit12. NZB-derived alleles at Lith22 and SM/J-derived alleles at Lith18 confer increased gallstone weight and incidence.

An interacting locus named Lith23 was detected at 13 cM on mouse Chromosome 11 near D11Mit152. SM/J-derived alleles at Lith23 and Lith19 confer increased gallstone weight.

Suggestive linkage to gallstone presence mapped to 26 cM on mouse Chromosome 17 near D17Mit177 (LOD=2.2). NZB/BlNJ-derived alleles at this locus confer increased gallstone incidence. Previously identified gallstone QTL Lith3 (3.5 cM) maps near the suggestive locus.

References

• Original: J:97646 Lyons MA, et al., Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM. Mamm Genome. 2005 Mar;16(3):152-63
• All: 1 reference(s)