Understanding the genetic architecture of glaucoma and its endophenotypes

• Main Author: Nag, Abhishek
• Other Authors: Hammond, Christopher John ; Hysi, Pirro
• Published: King's College London (University of London) 2016
• Subjects: 617.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695771

Heritability estimates for glaucoma and its endophenotypes [intraocular pressure (IOP) and vertical cup-to-disc ratio (VCDR)] indicate that genetic factors determine a significant part of the susceptibility to glaucoma or variance of its endophenotypes. Identification and characterization of glaucoma susceptibility genes will therefore help strengthen our understanding and provide insights into novel mechanisms underlying glaucoma pathogenesis. The GWAS era saw a surge in the identification of susceptibility genes for glaucoma and its endophenotypes. As has been the experience with most other complex human traits, the genetic variants identified so far collectively explain only a minority of glaucoma’s estimated heritability. The scope of this thesis is to understand the role of some of the possible determinants of the unexplained heritability of glaucoma using an endophenotype-based approach, which would in turn help build a more complete picture of its underlying genetic architecture. Findings of several individual study GWAS so far suggest that common genetic variants determine part of the genetic architecture of the glaucoma endophenotypes. In order to boost the power to detect some of the common genetic variants that might still remain unidentified, a large international collaborative effort named the International Glaucoma Genetics Consortium (IGGC) was established. Findings related to the investigation of the glaucoma endophenotypes in the IGGC have been described in this thesis. The role of structural genetic variation such as copy number variation (CNV) has been under-explored with relation to glaucoma. The hypothesis that CNVs might influence part of the susceptibility to glaucoma was therefore investigated and has been described in this thesis. Low frequency (rare) single nucleotide variants (SNVs) with intermediate effect size, which were neither common enough to be tagged in GWAS nor did they have effects strong enough to be captured by linkage studies, might determine a part of the unexplained genetic architecture of glaucoma. The role of this class of variants has been explored using a unique dataset of ~2000 subjects from the TwinsUK cohort that have had their whole genome sequenced as a part of the UK10K project. This thesis describes the various analytical strategies that have been explored to ascertain their role in relation to the glaucoma endophenotypes, and the findings pertaining to them. Finally, this thesis also discusses the potential implications of the novel findings obtained, and makes suggestions for future work in this field in order to build on our understanding of the genetic basis of glaucoma.