A Quantitative Traits Approach to Find Glaucoma Genes

Project Summary. Eye doctors diagnose patients with glaucoma by taking measurements of key features of the eye that are quantitative or numerical. Some of these quantitative features of glaucoma are eye pressure (measured in mm Hg), thickness of the cornea (measured in microns), the shape of the optic nerve (measured as the cup-to-disc ratio); and the extent of vision loss. The genes that control the magnitude of quantitative features of glaucoma likely contribute risk for developing disease.

The primary goal of this project is to identify the genes that control quantitative traits of glaucoma.

Subjects of the OHTS Genetics Study

Ocular Hypertension. Eyes are filled with fluid called aqueous humor that is under pressure. On average the pressure in the eye is around 15 mm Hg and eye pressure in most eyes falls within a limited range (between 9 and 21 mm Hg). When eye pressure is above this range, it is called ocular hypertension. Around 3% to 8% of Americans over the age of 40 have ocular hypertension.

Those with high pressure in their eyes (ocular hypertension) develop glaucoma more often than those with lower eye pressure.

ohtslogo.gifOcular Hypertension Treatment Study.
The Ocular Hypertension Treatment Study (OHTS) is a large treatment trial that was sponsored by the National Eye Institute. Prior to this study, it was unclear if giving pressure-lowering medicines to individuals with ocular hypertension reduced their risk for later developing glaucoma.

The goal of the OHTS was to determine if treating individuals with ocular hypertension with pressure lowering medicines reduces their risk for developing glaucoma in the future. A total of 1637 subjects with ocular hypertension were enrolled in the OHTS. At the time of enrollment in the study none of the subjects had signs of glaucoma – they only had high eye pressure. Half of the subjects with ocular hypertension received pressure-lowering medicines, while the other half received a placebo. Both groups of subjects were followed over ten years to see if pressure-lowering medicines prevented some ocular hypertension subjects from getting glaucoma. At regular intervals members of the study received eye exams to see if they had developed glaucoma.

The major discovery of this treatment trial was that giving pressure-lowering medicines to those with ocular hypertension does in fact significantly reduces their risk for getting glaucoma.

More about the results of the OHTS is available at the OHTS center.

The Ocular Hypertension Treatment Study has been completed. However, 1,077 of the 1,636 subjects in this study contributed DNA samples for use in our studies of the genetics of glaucoma.

Quantitative Traits of Glaucoma


During the course of the Ocular Hypertension Treatment Study several quantitative features of glaucoma were measured on 1,636 study subjects. These quantitative traits include:
  • Eye pressure (measured in mm Hg)
  • Thickness of the cornea (measured in microns)
  • Optic nerve shape (measured as the cup-to-disc ratio)

Previous studies have shown that the magnitude of eye pressure, corneal thickness, and features of the optic nerve are determined to a large degree by the action of genes – genes that have not yet been identified.

Extremes of these quantitative features (such as high eye pressure, thin corneas, and large cup-to-disc ratio) are known to confer significant risk for glaucoma.

As a result, it is likely that the same genes that control the magnitude of these quantitative traits may also confer risk for developing glaucoma.

The goal of this project is find the genes that control these quantitative features of glaucoma.

Using Association Studies to Find Disease-Causing Genes


Association studies search for differences in the genomes between patients with a disease (i.e. with glaucoma) and normal control subjects (i.e. with no glaucoma). These differences help researchers map the location of disease-causing genes in the genome.

Association studies are effective in finding disease-causing genes when the disease can be traced to mutations that arose in a few common ancestors or founders. Those with disease today are descendants from common ancestors and are distant relatives.

ancestralMutation.png

This diagram does a good job of illustrating association studies. The blue rectangle at the upper left corner represents the ancestor’s chromosome and the “X” represents a disease-causing mutation. Descendents of this person that inherit the portion of the blue chromosome with the mutation also inherit the disease as shown on the right part of the diagram.

Descendents that inherit the piece of their ancestor’s chromosome (blue segments) that contain the ancestral mutation (represented by the X) also inherit neighboring marker alleles from their founder. Consequently these marker alleles are more common in those with disease than in controls.

The goal of an association study is to scan the genome for regions in which patients have different marker allele frequencies than controls (the blue segment indicated with arrow at the bottom of the diagram). These regions may contain an ancestral disease-causing mutation.

Association study of participants in the OHTS


The goal of this project is find the genes that control these quantitative features of glaucoma. Rather than search for genes that directly cause glaucoma, we are using an association study to identify the genes that cause extremes of features of glaucoma listed below:
  • Eye pressure (measured in mm Hg)
  • Thickness of the cornea (measured in microns)
  • Optic nerve shape (measured as the cup-to-disc ratio)

Measures of these features have been collected from participants in the OHTS.

DNA samples from 1,077 participants in the OHTS are currently being tested for 1,200,000 genetic markers evenly distributed across the entire genome.

We will compare the magnitudes of each quantitative trait with genetic markers. The goal of this study is to map the location of the genes that control the magnitude of eye pressure, corneal thickness, and optic nerve shape. These genes may also be important risk factors for developing glaucoma.
The goal of this project is find the genes that control these quantitative features of glaucoma.

RESEARCH TEAM

fingert1.jpg John Fingert, M.D., Ph.D.
Principal Investigator
University of Iowa
Kass.jpg Michael Kass, M.D.
Co-Investigator
Washington University
Scheetz.jpg Todd Scheetz, Ph.D.
Co-Investigator
University of Iowa
Gordon.jpg Mae Gordon, Ph.D.
Co-Investigator
Washington University
Huan.jpg Jian Huan, Ph.D.
Co-Investigator
University of Iowa
Anderson.jpg Michael G. Anderson
Co-Investigator
University of Iowa
Wang.jpg Kai Wang, Ph.D.
Co-Investigator
University of Iowa

Funding Support for the Association Study of Participants of the OHTS

Funding support for the genetic studies of the Ocular Hypertension Treatment Study participants has been awarded by the National Eye Institute (R01EY018825).

NEI.jpg
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