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Webinar
Summary
Myopia is a common refractive error in which distant objects appear blurred, typically because the eye is elongated relative to its optical power. Myopia has emerged as an important global public health challenge, with rapidly increasing prevalence specially in East and Southeast Asian regions. Myopia is a complex condition, and its development is influenced both by genetic and environmental factors, but for many candidate genes, their precise role and mechanisms remain poorly understood. Genes on the X chromosome are typically not included in the large genome-wide association (GWAS) meta-analysis studies on myopia, even if the most frequently reported Mendelian early onset high myopia (eoHM) cases are associated with two genes on the X-chromosome; MYP1 and MYP26. One such gene is ARR3, an X-linked gene which encodes a cytoplasmic regulatory protein expressed in cone photoreceptors, have been associated with eoHM, especially in females. Earlier work has focused on ARR3 variants in families with eoHM. Despite these initial findings, it is unclear how specific missense variants might alter RNA splicing and, how this, in turn affects the encoded protein and whether ARR3 variants also play a role to mild-to-moderate myopia referred to as common or school myopia remains unclear.
The goal of this PhD thesis is to understand how ARR3 missense variants are related to myopia, including eoHM and their possible contribution to common myopia. By combining large-scale genetic data from gnomAD, and UK Biobank (a large, deeply phenotyped cohort of ~500,000 participants from the UK), bioinformatic and in-silico analyses, statistical analyses, and laboratory experiments on RNA splicing using minigene assays, the work aims to assess whether ARR3 variants may play a role in susceptibility to common myopia, to determine if and how they affect splicing, and to investigate whether their associations with refractive error differ by sex.
Main supervisor:
Professor Rigmor Baraas, USN
Co-supervisors:
Ph.d./gjesteforsker Lene Hagen, USN
Associate Professor Stuart Gilson, USN
Professor Maureen Neitz, University of Washington
Evaluators:
External member: Professor Christina Zeitz, Sorbonne University
Internal member: Associate Professor Mona Sæbø, USN