Experiment
Linkage analysis was performed in a genome wide search for loci influencing HDL-cholesterol; 282 F2 mice, from a (MRL/MpJ x SM/J)F2 cross, were genotyped for 259 markers.
MRL/MpJ mice were statistically higher in HDL when compared with SM/J, F1, RF1, and F2 mice in both males and females. SM/J mice were statistically lower in HDL when compared with F1, RF1, and F2 mice in males and females. No difference was observed between the two populations of F1 mice (F1 and RF1) indicati ng that HDL was not affected by an imprinted gene, a gene located on the X chromosome, or mitochondrial DNA in this cross.
QTL mapping revealed a significant HDL QTL (Apoa2) on Chromosome 1, LOD=31.3, peaking at 177.6Mb, with a 95% confidence interval between 170.5Mb - 181.8Mb. In TABLE 2 this QTL is labled as Hdlq15. The high allele at this locus was the MRL/MpJ allele, inherited in an additive mode.
12.11.2014 Curator's note: Hdlq15 was originally mapped in J:88486 in 2004 using an (C57BL/6J x 129S1/SvImJ)F2 intercross, which differs from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Hdlq100.
The high LOD score for the Hdlq100 QTL was attributed to the Apoa2 locus. Therefore a QTL analysis for each model was done afteradding the closest SNP [rs13476248] to Apoa2 as a covariate. The phenotype was renamed HDLApoa2, HDL adjusted for the Apoa2 locus. After adjusting the HDL level for the Apoa2 locus additional QTL were found.
An HDL QTL detected on Chromosome 11 at 71.7Mb displayed a suggestive LOD=2.4 before adjusting for the Apoa2 locus. After the adjustment, the LOD score achieved signifcance at LOD=4.1. The QTL was labeled Hdlq81 and mapped to a 95% confidence interval between 56.9Mb-90.6Mb. The high strain allelewas the MRL/MpJ allele, inheritied in a dominant mode. The closest marker was rs3024185.
A second QTL, detected on Chromosome 18 at 68.6Mb displayed a suggestive LOD=3.5 before adjusting for the Apoa2 locus. After the adjustment, the LOD score achievedsignifcance at LOD=4.4. The QTL was labeled Hdlq82 and mapped to a 95% confidence interval between 58.5Mb-81.0Mb. The high strain allele was also the MRL/MpJ allele, inheritied in a dominant mode. The closest marker was rs29559992. A novel nonsynonymous polymorphism supported Lipg as the gene for this QTL.
A suggestive QTL, LOD=2.5 was identified on Chromosome 10 at 60.0Mb before adjusting for the Apoa2 locus. The LOD was non significant in analysis following the adjustment.
A female-specific QTL was detected on Chr 13 at 63.8Mb, LOD=3.8 before adjusting for Apoa2 and LOD= non significant after the adjustment.
Four additional QTL were identified after the adjustment for the Apao2 gene that had not appeared with any significance in the previous analysis.
Two suggestive QTL were identified, one on Chr 1 at 124.5Mb, LOD=2.5; and another on Chr 3 at 71.3Mb, LOD=2.2.
Two significant QTLs were identified:
Hdlq78 on Chromosome 4, peaked at 38.6 Mb, with a 95% confidence interval between 3.5Mb-58.3Mb, LOD=3.8. The high strain allele was the SM/J allele, inherited in an additive mode of inheritance. The closest marker was rs3702229. A difference in the expression of gene Abca1 in liver tissue supported it as the QTL gene for this QTL.
Hdlq79, on Chromosome7,peaked at 56.3Mb, with a 95% confidence interval between 27.0Mb -124.1Mb, LOD=4.6 after adjusting for Apoa2. The high strain allele was the MRL/MpJ allele, inheritied in an additive mode. The closest marker was rs3663313.
Authors include mention of QTL Hdlq80, detected on Chromosome 7 at 58.2cM with a nonsignificant LOD, in TABLE 2. The legend cites this QTL as overlapping at QTL found in unpublished data [Su et al.] using a C57BL/6J x NOD/ShiLtJ cross.
In pairwise analysis a QTL was identified interacting with the chromosome 1 QTL (Hdlq100)
on Chr7 at 58.2cM (Hdlq80).
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