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

Samuel Fowler; Tengfei Wang; Daniel Munro; Aman Kumar; Apurva S Chitre; T J Hollingsworth; Angel Garcia Martinez; Celine L St Pierre; Hannah Bimschleger; Jianjun Gao; Riyan Cheng; Pejman Mohammadi; Hao Chen; Abraham A Palmer; Oksana Polesskaya; Monica M Jablonski

doi:10.3389/fgene.2022.1029058

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

Front Genet. 2023 Jan 30:13:1029058. doi: 10.3389/fgene.2022.1029058. eCollection 2022.

Authors

Samuel Fowler¹, Tengfei Wang², Daniel Munro^{3

4}, Aman Kumar¹, Apurva S Chitre³, T J Hollingsworth¹, Angel Garcia Martinez², Celine L St Pierre³, Hannah Bimschleger³, Jianjun Gao³, Riyan Cheng³, Pejman Mohammadi^{4

5}, Hao Chen², Abraham A Palmer^{3

6}, Oksana Polesskaya³, Monica M Jablonski¹

Affiliations

¹ Hamilton Eye Institute Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United states.
² Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, Tennessee, United states.
³ Department of Psychiatry, University of California, San Diego, San Diego, California, United states.
⁴ Department of Integrative Structural and Computational Biology, Scripps Research, San Diego, California, United states.
⁵ Scripps Research Translational Institute, Scripps Research, San Diego, California, United states.
⁶ Institute for Genomic Medicine, University of California, San Diego, San Diego, California, United states.

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.

Keywords: eQTL analysis; genome-wide association study; heterogeneous stock rats; intraocular pressure; primary open angle glaucoma.

Grants and funding

R01 GM140287/GM/NIGMS NIH HHS/United States