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Samuel Fowler, Tengfei Wang, TJ Hollingsworth, Angel Garcia Martinez, Jie Ni, Dan Munro, Hao Chen, Abraham A Palmer, Oksana Polesskaya, Monica M Jablonski; Genome-wide Association Study Finds Multiple Loci Associated with Intraocular Pressure In HS Rats. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1516.
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Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. It is associated with multiple disease processes with primary open angle glaucoma (POAG) being the most prevalent. Due to its complex, multifactorial nature, genetic predisposition is not completely understood, and a standardized animal model has yet to be developed for POAG. Heterogenous stock (HS) outbred rats is a multigenerational outbred population derived from eight fully sequenced founder strains. This population is ideal for genome-wide association studies (GWAS) due to most genetic variants being common, access to a large collection of tissue samples, and the large allelic effect size compared to human studies. The purpose of this study was to use HS rats to identify genetic loci underlying elevated IOP.
Both male and female HS rats (N=1812) were used in the study with genotyping by sequencing conducted on all subjects. We mapped quantitative trait loci (QTLs) for IOP phenotypes and SNP heritabilities were estimated. We used permutation to determine the threshold for significance using an empirical p value of 0.05. Linear mixed model was used to control for the complex family relationships of the HS rats.
GWAS identified three genome wide significant loci for elevated IOP located on chromosomes 1, 5, and 16. The QTLs contained 18 genes in total. Only one of these genes has been previously associated with human POAG.
This study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential candidate genes for future functional testing. GWAS is a powerful method for identifying genome regions which harbor variants responsible for the variation in quantitative traits, such as IOP. The identification of three independent QTLs in a relatively small sample size is promising for continued future findings as the sample population grows. Additional studies are ongoing to narrow the list of candidate genes in these intervals.
This is a 2021 ARVO Annual Meeting abstract.
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