Genetic Evidence for Differential Regulation of Corneal Epithelial and Stromal Thickness

Demelza R Koehn; Kacie J Meyer; Michael G Anderson

doi:10.1167/iovs.15-17179

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Genetic Evidence for Differential Regulation of Corneal Epithelial and Stromal Thickness

Journal article

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Peer reviewed

Genetic Evidence for Differential Regulation of Corneal Epithelial and Stromal Thickness

Demelza R Koehn, Kacie J Meyer and Michael G Anderson

Investigative ophthalmology & visual science, Vol.56(9), pp.5599-5607

08/2015

DOI: 10.1167/iovs.15-17179

PMCID: PMC4553932

PMID: 26305532

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https://doi.org/10.1167/iovs.15-17179View

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Abstract

Central corneal thickness (CCT) is a quantitative trait associated with keratoconus and primary open-angle glaucoma. Although CCT is highly heritable, known genetic variations explain only a fraction of the phenotypic variability. The purpose of this study was to identify additional CCT-influencing loci using inbred strains of mice. Cohorts of 82 backcrossed (N2) and 99 intercrossed (F2) mice were generated from crosses between recombinant inbred BXD24/TyJ and wild-derived CAST/EiJ mice. Using anterior chamber optical coherence tomography, mice were phenotyped at 10 to 12 weeks of age, genotyped based on 96 genome-wide single nucleotide polymorphisms (SNPs), and subjected to quantitative trait locus (QTL) analysis. In an analysis of total CCT among all mice, two loci passed the significance threshold of P = 0.05. These were on Chr 3 and Chr 11 (Cctq4 and Cctq5, respectively). A third locus of interest was identified in a two-dimensional pairwise analysis; this locus on Chr 14 (Cctq6) exhibited a significant additive effect with Cctq5. Independent analyses of the dataset for epithelial and stromal thickness revealed that Cctq4 is specific to the epithelial layer and that Cctq5 and Cctq6 are specific to the stromal layer. Our findings demonstrate a quantitative multigenic pattern of CCT inheritance in mice and identify three previously unrecognized CCT-influencing loci: Cctq4, Cctq5, and Cctq6. This is the first demonstration that distinct layers of the cornea are under differential genetic control and highlights the need to refine the design of future genome-wide association studies of CCT.

Corneal Stroma - metabolism

Glaucoma, Open-Angle - genetics

Mice, Inbred C57BL

Genotype

Glaucoma, Open-Angle - pathology

Male

Chromosome Mapping

Epithelium, Corneal - pathology

Phenotype

Animals

Corneal Stroma - pathology

Epithelium, Corneal - metabolism

Female

Glaucoma, Open-Angle - metabolism

Mice, Inbred DBA

Mice

Polymorphism, Single Nucleotide

Quantitative Trait Loci

Corneal Pachymetry

Disease Models, Animal

Details

Title: Subtitle: Genetic Evidence for Differential Regulation of Corneal Epithelial and Stromal Thickness
Creators: Demelza R Koehn - Department of Molecular Physiology and Biophysics University of Iowa, Iowa City, Iowa, United States
Kacie J Meyer - Department of Molecular Physiology and Biophysics University of Iowa, Iowa City, Iowa, United States
Michael G Anderson - Department of Molecular Physiology and Biophysics University of Iowa, Iowa City, Iowa, United States 2Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States 3Center for the Prevention and Treatment of Visual Lo
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.56(9), pp.5599-5607
Publisher: United States
DOI: 10.1167/iovs.15-17179
PMID: 26305532
PMCID: PMC4553932
ISSN: 0146-0404
eISSN: 1552-5783
Grant note: EY017673 / NEI NIH HHS F32 EY021436 / NEI NIH HHS EY021436 / NEI NIH HHS R01 EY018825 / NEI NIH HHS EY018825 / NEI NIH HHS R01 EY017673 / NEI NIH HHS
Language: English
Date published: 08/2015
Academic Unit: Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
Record Identifier: 9984025364702771

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