What constitutes a healthy eye? Investigations of genetic and environmental influences in eye disease

Research output: ThesisDoctoral Thesis

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With its unique tissue composition and easy-to-measure physiological characteristics (ocular biometry), the eye serves as a window for discovering the genetic and environmental factors that determine its structure and status in health and disease. Revolutionary findings through multiple omic technologies have already allowed us to collect vast amounts of ocular data at an individual level (Chapter 2). A major bottleneck of biological discovery using this immense volume of data is emerging at the computational level. Cloud computing is confirmed to be an efficient and cost-effective alternative for analysis of large genomic datasets in small and medium-sized research laboratories with limited computational capacity (Chapter 3). This finding is promising especially given that data collection and analysis are the basis for individualised ophthalmic care, which requires tailoring of treatment and preventative measures according to individual genomic characteristics and environmental influences. The work required for individualising ophthalmic care has many steps and can be described in layers similar to a geographic information system. The bottom layer of this model consists of identifying genetic factors that cultivate ocular disease. Next layers contain various studies that build a bridge between a genotype and a phenotype. One of these layers is determining environmental exposures from conception onwards. The objective of the present thesis is to determine the genetic and environmental risk factors relating to eye disease.

One method to achieve this goal is pooling data from large population-based cohorts longitudinally and data mining through various techniques. With this in mind, the 20- year follow-up the Western Australian Pregnancy Cohort (Raine) Eye Health Study was conceived to collect multi-scale data to characterize ocular biometric parameters and determine the baseline prevalence and risk factors of common eye diseases in a young adult population born in Western Australia. Dissecting components of complex ocular diseases relies on phenotypic variation that necessitates accurate phenotyping in assembly of such large volume of data. Therefore, standardized methodology and practical guidelines were described at the beginning of this work to utilize in current and future eye research (Chapter 4).

In the 20-year-old individuals, the prevalence of most eye diseases was low, except myopia. This was in line with the increased prevalence of myopia worldwide, highest in East-Asian countries. Although simple myopia itself is a non-sight threatening condition and can be corrected with spectacles, contact lenses and refractive surgery, high myopia is commonly associated with debilitating eye diseases such as glaucoma, maculopathies and retinal detachment. Hence, any preventative measure or treatment modality will have benefits not only at individual level but also for the ocular health care system.

Myopia is due to imbalance of ocular biometry, mainly axial length and corneal curvature. However, higher levels of monochromatic aberrations were found to be associated with increased severity of myopia in young adults. This suggests that while some biometry has a major role in myopia occurrence, other parameters have a small and substantial effect (Chapter 5).

Disproportionate ocular biometry in myopia is a consequence of interactions between the genes and the environmental risk factors an individual is exposed to at various stages of life including the perinatal period and early childhood. We confirmed that paediatric has no effect on levels of myopia in young adulthood (Chapter 6). Time spent outdoors during childhood is suggested to be protective against myopia development, although the exact mechanism of this effect remains unknown. One of the challenges of studies investigating these mechanisms is that ocular sun exposure cannot be measured directly and quantitatively. Therefore biomarkers representing this measurement need to be identified and utilised instead. Conjunctival UV autofluoresence (CUVAF) can be an ideal biomarker for this purpose. However, the following characteristics must be considered when used: [1] prevalence of CUVAF increases with increasing latitude (toward equator); [2] although it is largely environmental, genes also play a significant role in its development. Notably a single polymorphism (SNP) in solute carrier family 1, member 2 (SLC1A5) gene is associated with CUVAF, suggesting that some individuals have higher risk than the others because of their genetic composition (Chapter 7). Vitamin D pathways were hypothesised to be involved in myopia development. Myopic individuals were found to have lower levels of serum vitamin D. Although this association could be evidence for an underlying mechanism, it could be simply a biomarker of whole-body sun exposure (Chapter 8).

Although the relationship of corneal curvature and axial length is the main driver of the refractive status and myopia development in childhood, uncorrected corneal astigmatism may inhibit emmetropisation and cause myopia during ocular growth. Hence dissecting the genetics of corneal curvature and corneal astigmatism, which are highly heritable, may help us to understand uncoordinated growth of refractive components in myopia. A limited number of genetic studies of corneal astigmatism and corneal curvature have been performed. The only published genome-wide association study (GWAS) for corneal astigmatism was from a Singaporean Asian population. We were unable to replicate the reported association of corneal astigmatism and the platelet-derived growth factor receptor alpha (PDGFRA) locus in Australians of Northern European ancestry. The same variant has also been implicated in corneal curvature in the same Singaporean population. We searched for the same variant in our cohorts and were able to replicate previous findings (Chapter 9).

In this research, a number of important associations with myopia are identified utilising mainly a cohort of healthy young adults. Although translation of these findings requires extensive efforts and completion of multiple stages, the milestones achieved in other complex diseases give us the hope that similar advancements are feasible for myopia. However, now, the next phase of studies should focus on replication studies in other cohorts to validate these findings.

Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2015


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