Idohtq^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Idohtq^C57BL/6J
• Name: iris defect with ocular hypertension QTL; C57BL/6J
• MGI ID: MGI:5896586
• QTL: Idohtq Location: Chr4:80752467-93112991 bp Genetic Position: Chr4, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

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

J:234169

Glaucoma is a heterogeneous group of diseases characterized by death of retinal ganglion cells, specific visual field deficits and optic nerve degeneration. Elevated intraocular pressure (IOP) is often associated with glaucoma and is one of the strongest known risk factors. An inbred strain of mice, YBR/EiJ (YBR), exhibit a progressive age-related pigment-dispersing iris disease characterized by stromal atrophy. Subsequently these mice develop elevated intraocular pressure and glaucoma.

To map genes controlling iris disease and high IOP, glaucoma susceptible YBR/EiJ were crossed with glaucoma resistant C57BL/6J (B6) mice. F1 mice were then backcrossed to the YBR parental strain generating more than 90 N2 progeny. The resulting progeny were aged up to 17 months and clinical examination of their eyes (slit-lamp examination) was performed every 2 months between 3 and 17 months. IOP was measured at multiple time points between the ages of 8 and 17 months.

Initial genotyping was performed using over 116 genome-wide single nucleotide polymorphic markers that differentiated between the YBR and B6 strains, spaced at app 20 Mb intervals.

A genome-wide one-dimensional QTL scan was performed to identify the chromosomal loci regulating IOP. R/QTL software version 1.14-2 was used for QTL analysis. Fine mapping of a crucial YBR chromosome 17 region (69-86 Mb) was performed using MIT markers distinguishing the YBR from the B6 genome (NCBI37/mm9).

QTL analysis using IOP values as a continuous trait detected two important chromosomal regions: one on Chromosome 4 and one on Chromosome 17. Next, to delineate the effect of iris disease from other factors contributing to high IOP, a QTL analysis was performed on a cohort of the N2 progeny with a black coat; mice heterozygous for the Tyrp1^b region and that do not exhibit the disease. This analysis revealed that only the YBR chromosome 17 locus significantly contributed to the generation of high intraocular pressure; demonstrating that a gene within the Chr 17 locus contributed to high IOP in the absence of the iris disease.

QTL Idohtq (iris defect with ocular hypertension QTL) mapped to a critical interval between 80,834,230 - 93,224,754 bp on Chromosome 4 with a LOD score of 3.64 on Chromosome 4 (authors state that this is likely to be Tyrp1^b).

QTL Ohtq (ocular hypertension QTL) mapped to a critical region between 73,461,956 and 86,112,456 bp on Chromosome 17 with a LOD score of 5.14. The recessively inherited YRB allele increased risk at both loci.

Further analysis of the implicated chromosomal regions using correlation analysis (linear regression) demonstrated that mice homozygous for recessive YBR loci on either Chromosome 4 or Chromosome 7 developed slightly higher IOP compared to mice heterozygous for each of the YBR loci. Using a full ANOVA model interactions between the two loci were tested. Results demonstrated that the peak markers at Idohtq and Ohtq did not interact.

Next, an additive model was used to test the combined effect of markers at Idohtq and Ohtq on IOP outcome. Exclusion of either the Chr 4 or Chr 17 region from the additive model caused a significant decrease in the magnitude of IOP and frequency of mice developing IOP.

Based on statistical modeling the results were interpreted as follows: the YBR chromosome 4 locus primarily dictates the iris disease phenotype, and the deposited pigment and debris impact on drainage tissue, contributing to angle closure and high IOP. The YBR Chromosome 17 locus acts through a distinct mechanism (not involving iris disease) to induce high IOP. Although these loci underlie distinct pathogenic processes, they act in an additive fashion to promote an elevation of IOP.

References

• Original: J:234169 Nair KS, et al., YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17. Dis Model Mech. 2016 Aug 1;9(8):863-71
• All: 1 reference(s)