Getting to the root of MacTel: joint dissection of genetic risk loci and ocular phenotypes

Abstract

Purpose : Macular telangiectasia type 2 (MacTel), is a rare and often underdiagnosed degenerative eye disease that may results in blindness. MacTel patients present with different clinical signs, usually between the ages of 40-60, such as loss of retinal transparency, pigment plaques, abnormal capillaries and parafoveal telangiectasias, resulting in visual acuity and quality of life loss. Historically, we carried out a genome-wide association study and discovered the first five genetic loci involved in this disease. These loci belong to multiple biological pathways, with the top locus previously associated to retinal vasculature calibre and the other four with the glycine/serine metabolism pathway. In this study, we wanted to discover whether these genetic loci are associated with particular MacTel clinical phenotypes.

Methods : We analysed phenotypic data from the MacTel Natural History Study conducted from 2005 to 2015 on 1094 MacTel cases and 98 controls. After multiple imputation to infer missing data we reduced the initial 200 phenotypes to 20 endophenotypes using methods such as factorial analyses. These endophenotypes encompass macular abnormalities as well as visual acuity and vision health related quality of life status estimated through the NEI VFQ-25. We then analysed the association between the genetic risks and the endophenotypes in 500 MacTel patients, that had genetic data available, using linear mixed models.

Results : Genetic loci implicated in the glycine and serine pathway were associated with an increased loss of retinal transparency (b=0.076, p-value=0.001), retinal pigment plaques (b=0.085, p-value=0.005) and breaks of the IS/OS layer (b=0.052, p-value=0.006). The same loci were found to be associated with a decrease of retinal thickness (b= -0.086, p-value=0.002). On the contrary, the top locus in the GWAS study was associated with an increase in retinal thickness (b=0.036, p-value=0.001). Our analysis also suggests a relationship between genetic risk, visual acuity and vision health related quality of life.

Conclusions : Our results show that the set of complex phenotypes in MacTel can be dissected by the genetic loci, partitioning both the genetic and diagnostic aetiologies. Further work will use these results to identify early signs of the disease and to identify the genes underpinning the GWAS loci and their mechanism. This will lead to better prognosis and future treatments.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.