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Discovery of genetic determinants for refractive error

Shah, Rupal Lalit ORCID: 2018. Discovery of genetic determinants for refractive error. PhD Thesis, Cardiff University.
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Refractive errors such as myopia are the leading cause of reversible visual impairment worldwide with their prevalence rapidly increasing, resulting in greater burden on public health services. The aim of this series of investigations was to leverage the latest statistical methods and large-scale cohorts available in order to develop our understanding of the genetic determinants for the refractive error traits of spherical equivalent, corneal astigmatism and refractive astigmatism. Investigation of genetic variants on the X-chromosome, a region often neglected in genome-wide association studies (GWAS), identified four genes demonstrating association in a gene-based analysis of spherical equivalent for a cohort of teenagers. Meta-analysis of GWAS results for corneal astigmatism including European and Asian ancestry cohorts performed on behalf of the CREAM consortium successfully replicated the previously identified association near the PDGFRA gene (lead variant: rs7673984, odds ratio = 1.12, P = 5.55 × 10−9). The availability of data from the UK Biobank facilitated the largest GWAS for corneal and refractive astigmatism performed to date (N = 86,335 and 88,005 respectively). Here, GWAS for these traits identified four and two novel loci associated with corneal and refractive astigmatism respectively. Each of these loci had previously been associated with other ocular traits including myopia. Phenotypic variance explained by common genetic variants was relatively low for corneal and refractive astigmatism at ~6% and ~5% respectively, thus proposing a greater role for rare variants in explaining astigmatism variance due to genetics. Lastly, in order to link identified variants and genes functionally influenced in myopia development, several candidate myopia genes identified from a primate myopia model demonstrated enrichment with refractive error associated variants in human samples. Overall, the findings from these investigations are a starting point in guiding further research into the complex biological mechanisms underlying refractive error development.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Optometry and Vision Sciences
Subjects: R Medicine > RE Ophthalmology
Uncontrolled Keywords: Corneal astigmatism, Genetics, GWAS, Heritability, Myopia, Refractive astigmatism, Refractive error
Date of First Compliant Deposit: 4 September 2018
Last Modified: 08 Nov 2022 11:22

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