Searching all of our genes for changes linked to glaucoma
Research details
- Type of funding: Early Career Investigator Award
- Grant Holder: Dr Pirro Hysi
- Institute: King’s College London
- Region: London
- Start date: October 2013
- End Date: December 2015
- Priority:
- Eye Category:
Overview
Glaucoma is the second most common cause of blindness worldwide. Although some genes have already been linked to glaucoma, they only explain some of the inherited part of the risk of getting it. This is down to the technology available, as well as not having the large numbers of study participants needed to get clear results given the very large number of potential genetic variations involved.
In this study, Dr Hysi has four main aims:
- To work on an international study that looks at genetic variations across the whole genome in what’s known as a ‘genome wide association study’ or GWAS. This type of study can pick up genetic variations that would be missed by only scanning a few likely genes.
- To find and study rare variations in genes and learn about which ones change the way the gene works in a way that leads to glaucoma.
- To work out how genes interact with each other to produce the changes seen in glaucoma.
- To develop new and improved ways to study changes to DNA structure in complex eye conditions.
Results from the study should takes us closer to personalised medicine based on the particular genetic variations individual patients have. At the moment the only treatment for glaucoma that works is lowering fluid pressure in the eye, but this doesn’t work for everyone, so we need new targets for treatment.
-
Scientific summary
Identification of genetic susceptibility factors for glaucoma through analysis of large scale genotype and sequencing data
Genome-Wide Association studies (GWAS) moved genetics research from hypothesis-driven candidate gene approaches towards a truly global study of disease. They have successfully identified thousands of genetic variations influencing many diseases. Early GWAS in glaucoma have found novel, interesting results, but there is scope for further improvement in their potential clinical utility. For example, GWAS have explained only a small portion of glaucoma heritability, due to higher than expected heterogeneity in disease architecture and incomplete mapping afforded by existing technologies. The current project addresses these two existing limitations, specifically in the field of glaucoma research, by a meta-analysis of GWAS of 34,000 subjects from around the world, for quantitative traits related to glaucoma. This will allow detection of genetic variants impossible by using any of the current cohorts on their own.
This project also takes advantage of whole-genome sequencing data available for more than 2,000 subjects to look at other variants of rarer frequency but with potentially stronger effects on glaucoma. This work will therefore identify variants affecting susceptibility to glaucoma all across the spectrum from rare variants with strong effect to weaker but more common risk polymorphisms. In addition
Dr Hysi is developing methodologies aimed at better identification and analysis of structural variations in the genome. These variations can be compared bio-informatically against the databases of known physiologic pathways, to better understand the pathophysiology of glaucoma.
-
Research update
So far, Dr Hysi’s work has found evidence that the workings of certain genes can be shared between different conditions that cause sight loss, such as short-sightedness (myopia) and glaucoma. He has found some interesting patterns in the way different genetic variations interact with each other and learned more about the links between rare and common variations that cause glaucoma.
-
Publications
- Bailey JNC, Loomis SJ, Kang JH, Allingham RR, Gharahkhani P, Khor CC, et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nature Genetics . 2016 Jan 11.
- Springelkamp H, Mishra A, Hysi PG, Gharahkhani P, Höhn R, Khor C-C, et al. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology. Genetic Epidemiolog. 2015 Mar; 39(3):207–16.
- Mahroo OA, Williams C, Hysi PG, Williams KM, Kailani O, Thompson J, et al. Interocular asymmetries in axial length and refractive error in 4 cohorts. Ophthalmology. 2015 Mar;122(3):648–9.
- Vehof J, Kozareva D, Hysi PG, Hammond CJ. Prevalence and risk factors of dry eye disease in a British female cohort. Br J Ophthalmol. 2014 Dec;98(12):1712–7.
- Hysi PG, Cheng C-Y, Springelkamp H, Macgregor S, Bailey JNC, Wojciechowski R, et al. Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet . 2014 Oct 46(10):1126–30.
- Hysi PG, Wojciechowski R, Rahi JS, Hammond CJ. Genome-wide association studies of refractive error and myopia, lessons learned, and implications for the future. Invest Ophthalmol Vis Sci. 2014 May;55(5):3344–51.
- Springelkamp H, Höhn R, Mishra A, Hysi PG, Khor C-C, Loomis SJ, et al. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process. Nat Commun. 2014;5:4883.