The Genetics of Common, Complex Diseases

Bailey, Jessica N. Cooke; Sobrin, Lucia; Wiggs, Janey L.

doi:10.1007/978-3-030-42634-7_151

Cited by 1 publication

(1 citation statement)

References 154 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of HS rats to study naturally occurring variations of IOP is beneficial in several ways. Numerous studies have demonstrated that phenotypic variation in humans is associated with both common and rare variants of varying effects ( Cooke Bailey et al, 2020 ; Craig et al, 2020 ; Gharahkhani et al, 2021 ). In HS rats, all variants are common, due to the design of this population, which allows the identification of associated variants using smaller sample sizes than those required for human GWAS.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%