Understanding the genetics and function of complex human retinal phenotypes

The human retina is the tissue at the back of the eye responsible for converting light stimulus into neuronal signal that can be interpreted by the brain. To perform this integral role within the central nervous system, the retina has a complex and layered structure, with each layer performing a vital step in the signal transformation process. Changes in the morphology of this structure are often a consequence of disease, which can affect the function of the eye. Better understanding of the genetics influencing this structure may teach us about the biological processes underlying these diseases as well as general eye development. The retina is imaged routinely in the clinic using optical coherence tomography (OCT), providing a non-invasive imaging technique that produces high-resolution, three-dimensional representations of the retina from which measures describing retinal morphology can be extracted. This thesis summarises my research into the genetic variation underlying retinal morphology. Firstly, I explored the morphology of the inner retina, whose thickness is used as a biomarker of glaucoma, using quantitative phenotypes extracted from OCT. I conducted genome-wide association studies (GWAS) of the thickness of the retinal nerve fibre layer and the ganglion cell inner plexiform layer to understand the genetic variation driving inner retinal morphology. I further explored the causal relationship between the inner retina and glaucoma using Mendelian randomisation analysis. I next performed GWAS of the thickness of the outer retinal layers, including both the component photoreceptor cell layers (the outer nuclear layer, inner segment, and outer segment), and the retinal pigment epithelium layer. I explored how genetic variation was affecting the outer retinal morphology at a higher dimension by looking for genetic variants that were differentially affecting the outer retinal thickness at the central macula compared to the peripheral macula. To further explore the rich dimensionality of OCT data, I developed several image analysis techniques to gain more granular information about the morphological variation being affected by the discovered genetic variants. In doing so I established a novel population level trait and examined its effect on visual acuity. In summary, this thesis provides a well-rounded and detailed look into the genetic variation underlying morphological variation of the retinal layers. As the largest study of retinal layer genetics of its kind, it offers insight into clinical ophthalmology and retinal development, and furthermore opens new avenues for clinical research.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Currant, Hannah

Advisor dc:contributor.advisor

• Birney, Ewan

• Genetics
• Retina
• Bioinformatics

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4952f30c-e50c-4cad-ab05-27c3f60a1c70/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.68762

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/321644