Genome-wide association study finds multiple loci associated with intraocular pressure in HS rats

Abstract

Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. Increased IOP is a major risk factor for most types of glaucoma, including primary open angle glaucoma (POAG). Investigating the genetic basis of IOP may lead to a better understanding of the molecular mechanisms of POAG. The goal of this study was to identify genetic loci involved in regulating IOP using outbred heterogeneous stock (HS) rats. HS rats are a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This population is ideal for a genome-wide association study (GWAS) owing to the accumulated recombinations among well-defined haplotypes, the relatively high allele frequencies, the accessibility to a large collection of tissue samples, and the large allelic effect size compared to human studies. Both male and female HS rats (N = 1,812) were used in the study. Genotyping-by-sequencing was used to obtain ∼3.5 million single nucleotide polymorphisms (SNP) from each individual. SNP heritability for IOP in HS rats was 0.32, which agrees with other studies. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to determine a genome-wide significance threshold. We identified three genome-wide significant loci for IOP on chromosomes 1, 5, and 16. Next, we sequenced the mRNA of 51 whole eye samples to find cis-eQTLs to aid in identification of candidate genes. We report 5 candidate genes within those loci: Tyr, Ctsc, Plekhf2, Ndufaf6 and Angpt2. Tyr, Ndufaf6 and Angpt2 genes have been previously implicated by human GWAS of IOP-related conditions. Ctsc and Plekhf2 genes represent novel findings that may provide new insight into the molecular basis of IOP. This study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential candidate genes for future functional testing.

Establishment and Application of a Novel Genetic Detection Panel for SNPs in Mongolian Gerbils

“…In comparison with microsatellites, single-nucleotide polymorphisms (SNPs) possess the advantages of widespread distribution, enhanced stability, simplified analysis, and high throughput capacity, rendering them more suitable as markers for genetic monitoring. SNP markers have been widely used in genetic evaluations in many kinds of laboratory animals, Genes 2024, 15, 817 2 of 11 such as mice [22][23][24][25] and rats [26][27][28][29]. They have been widely used in animal and plant breeding, disease-resistance gene markers, and the screening and identification of varieties of disease-related genes.…”

Genome-wide association study of delay discounting in Heterogenous Stock rats

“…HS rats are an outbred population derived from eight inbred founder strains and have been used extensively for GWAS of other phenotypes. [34][35][36][37] The high level of both genetic and phenotypic diversity of these rats makes this an ideal population to investigate complex neurobehavioral traits such as delay discounting and to identify associated genetic variants. 38,39 There is some debate about the most appropriate way to quantify delay discounting.…”