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H. Chen, H. Guan, H. Lu, M. M. Jablonski, R. W. Williams, L. Lu; Genetic Dissection of IOP Regulation. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2149.
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© ARVO (1962-2015); The Authors (2016-present)
To find the dominant factors and molecular biology mechanisms contributing to the elevation of intraocular pressure (IOP) in DBA/2J mice, a natural model of pigmentary dispersion syndrome (PDS) and pigmentary glaucoma (PG). We also constructed a genetic regulatory network for this phenotype.
Using an induction-impact tonometer (Tonolab) we measured the IOP of 3063 mice. Because IOP varies significantly during the life of a DBA/2J mouse, all mice were grouped according to age (1-2 months, 2-5 months, 6-9 months, 10-13 months and >13 month) and were comprised of 71 strains of BXD RI mice, two parental strains (C57BL/6J and DBA/2J), and two F1 strains (B6D2F1 and D2B6F1). We also measured gene expression levels in the eyes from these mice using an oligo microarray system. Subsequently we used quantitative trait locus (QTL) analysis to identify areas of the genome that regulate IOP. Candidate genes were identified using filters such as the density of SNPs and the mean expression levels. Moreover, correlation analyses were made and a gene regulatory network was constructed.
Interval mapping identified a significant QTL on Chr 5 in BXD mice aged 10-13 months, and two suggestive QTLs on Chr 3 and Chr 10 in BXD mice aged 1-2 months and 6-9 months, respectively. None of these QTLs corresponded to the position of Tyrp1 and Gpnmb, the genes that cause PDS in the D2 mouse. Within QTLs that we did identify, the list of candidate genes was narrowed and the highest priority candidates included three genes in the interval on Chr 5 between 14.2 and 18.8 Mb (i.e., Pclo, Cacna2d1, Hgf), 15 genes in the interval on Chr 3 between 103.0 and 113.0 Mb (i.e., Kcnd3, Ddx20, Rap1a, Adora3, Atp5f1, Wdr77, Ovgp1, Kcna2, Hbxip, Slc16a4, Rbm15, Kcnc4, Slc6a17, Csf1, Ntng1), and three genes in the interval on Chr 10 between 121.8 and 123.0 Mb (i.e., Ppm1h, Mon2, Usp15). Separate genetic networks were generated for regulation of baseline IOP and elevated IOP and included genes from several interesting functional groups.
This study demonstrates that the genetical genomics approach provides a powerful tool for mapping genes that regulate IOP. Moreover, it illustrates that Tyrp1 and Gpnmb indirectly cause IOP elevation. Importantly, other genes located within the QTL intervals we identified are directly responsible for elevated IOP. Genetic network analyses demonstrate that different genes regulate normal and elevated IOP levels.
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