Genomic Locus Modulating IOP in the BXD RI Mouse Strains

King, Rebecca; Liu, Ying; Wang, Jiaxing; Struebing, Felix L; Geisert, EE

doi:10.1534/g3.118.200190

Cited by 6 publications

(5 citation statements)

References 55 publications

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“…This is distinct from the locations of Tyrp1 and Gpnmb in the genome. It is also distinct from loci that have been demonstrated to modulate IOP (Chintalapudi et al, 2017;King et al, 2018a) and central corneal thickness (King et al, 2018b). Using data derived from younger aged mice (not shown), a similar quantitative trait locus (QTL) peak is not present, suggesting that the gene variant(s) responsible for modulating axon necrosis contribute to ON degeneration primarily at older ages, which is consistent with the age of onset of noncongenital glaucomas.…”

Section: Optic Nerve Necrosis Across the Bxd Familymentioning

confidence: 60%

“…These findings demonstrate ON axon necrosis is not linked to either Tyrp1 or Gpnmb and is therefore independent of two of the main genetic mutations known to contribute to pigmentary dispersion glaucoma in the D2 mouse. Interestingly, the chromosome 12 locus also does not overlap with other loci recently identified in the BXD family that modulate IOP (Chintalapudi et al, 2017;King et al, 2018a) or central corneal thickness (CCT, (King et al, 2018b)), both of which are risk factors for glaucoma (Investigators, 2000;Gordon et al, 2002;Medeiros et al, 2003;Group, 2007).…”

Section: Optic Nerve Necrosis Across the Bxd Familymentioning

confidence: 94%

“…Systems genetics is a scientific approach that collectively analyzes large cohorts of isogenic and fully sequenced individuals to evaluate relationships among SNPs, other sequence variants, molecular endophenotypes (Geisert et al, 2009;, cellular function and properties (e.g. RGC types and numbers (Williams et al, 1998)), rates of axonal degeneration, and classical clinical phenotypes such as IOP (Chintalapudi et al, 2017;King et al, 2018a), visual field loss, age, sex, and environmental cofactors. In the present study, we apply this general approach to ongoing studies of glaucoma using the BXD family of mice.…”

Section: Introductionmentioning

confidence: 99%

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Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

et al. 2020

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In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve crosssection were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of~18.5 (p genome-wide~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

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Section: Optic Nerve Necrosis Across the Bxd Familymentioning

confidence: 60%

Section: Optic Nerve Necrosis Across the Bxd Familymentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

et al. 2020

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“…The SNP heritability is expected to be somewhat lower than heritability estimated in twin studies or by using inbred strains. Heritability of IOP reported in human studies ranges from 0.39 to 0.64 ( Chang et al, 2005 ; Carbonaro et al, 2009 ; Renard et al, 2010 ), heritability estimated using BXD mouse strains was 0.31 and 0.35 ( Chintalapudi et al, 2017 ; King et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…demonstrated that IOP varied in 30 inbred strains, suggesting that IOP is a heritable trait in mice. A genetic study using 38 BXD recombinant inbred strains identified QTL on chromosome 8, and selected Cdh11 as a candidate gene (King et al, 2018). In another study, IOP was measured in a panel of 65 BXD strains, identifying a QTL on chromosome 5, with Cacna2d1 selected Frontiers in Genetics frontiersin.org as a candidate gene based on systems genetic approach (Chintalapudi et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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