Exome-wide analyses of glaucoma-related endophenotypes in 19,700 individuals

Abstract

Purpose : Glaucoma is a heterogeneous optic neuropathy in which rare coding and common non-coding genetic variants play a key role. Although the over 70 identified non-coding variants may be implicated in glaucoma pathogenesis through gene regulation, most were discovered by genome-wide association without in-depth exploration of the region for coding variants. We conducted an exome-wide study in 19,700 persons of European descent to discover and replicate new coding variants implicated in the pathogenesis of glaucoma

Methods : We used exome-wide sequence and array data of three independent European cohorts: The Rotterdam Study (RS), The Erasmus Rucphen Family study and the EPIC study (N~11,400). Three glaucoma-related endophenotypes were examined: disc area, vertical cup-disc ratio (VCDR) and intraocular pressure (IOP). Fixed-effect meta-analyses were performed and variants with P <1.0x10^-04 were selected for in silico replication in independent participants of the RS and the TwinsUK study (N~8300). To allow reliable replication of low-frequency variants, cohorts were imputed with the Haplotype Reference Consortium (HRC) reference panel. Based on the number of exonic variants in the discovery (N = 78,604), the P-value for exome-wide significance was 6.3x10^-07

Results : We identified one novel low-frequency missense variant in the MITF gene significantly associated with disc area (P=1.9x10^-07) and suggestive for VCDR (P= 1.1x10^-05). Other common coding variants in previously known regions were also associated with optic nerve parameters. Significant association with VCDR was found in proximity to previously reported non-coding variants annotated to DUSP1, SIX6, and CHEK2. For IOP, novel rare coding variants in RUSC1 and OR4N2 reached exome-wide significance in the discovery but were not present in the HRC imputations. Also for IOP, we found common coding variants in previously reported regions, including ARHGEF12 and MADD

Conclusions : We identify a novel missense low-frequency variant in the MITF gene implicated in disc area and VCDR. MITF regulates the differentiation of the retinal pigmented epithelium and has been implicated in murine microphthalmia. For IOP, we discovered four novel exonic variants for which replication is ongoing. Our analysis provides further new biologically relevant insights of the annotation and functional relevance of genome-wide associated signals

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