Variable threshold burden style rare-variant tests identify novel genes associated with refractive error in a large multi-ancestry cohort

Abstract

Purpose : Myopia is a complex refractive error trait with a rapidly increasing prevalence and visual burden world-wide. GWA studies have currently identified >500 common variants for refractive error, but they have not yet dissected many rare variants with potentially large effects. This study aimed to identify these variants using exome chip screening in a large multi-ancestry cohort.

Methods : A total of 10 population-based cohorts from CREAM were included in the current study and grouped into Indo-Europeans and East Asians. Exome array genotypes (Illumina HumanExome-12) were jointly called to increase the number of rare (i.e. MAF<1%) variants. Three other CREAM studies, the Raine Eye Health Study, Beaver Dam Eye study and EPIC-Norfolk, were used as replication cohorts.
Different approaches to analyses are useful because they have different strengths in their ability to identify candidate genes. We analyzed spherical equivalent (SER in diopters (D)) using the EMMAX version of the variable threshold (VT) test, which increases power on rare variants (compared to single variant tests) by creating a new gene-based marker. We meta-analyzed the p-values of all datasets (discovery and replication) together using the method described by Fisher, implemented in the R package metap. We conducted an IPA pathway analysis to assess enriched pathways and to prioritize genes based on predefined criteria.

Results : The total discovery study included 17,904 (13,037 Indo-European and 4,867 East-Asian) individuals with a mean (SD) SER of 0.01 (2.30) D. In the meta-analysis, which combined the VT results across all cohorts, 43 genes were found to be genome-wide significant (defined as ≤ 1 x10^-5). The most significant gene was GDF15 on chromosome 19 (P = 5.12 x10^-9). 40% of the identified genes showed an association with a human ocular disease, 21% evidence of human ocular expression and 12% demonstrated an ocular phenotype in knock-out mice. Cell cycle processes and embryonic development were implicated as important underlying pathways. Among the most biologically plausible gene hits were CHST6 and GRHL2 (P=8.99x10^-7 and P= 1.42x10^-6 respectively); both associated with corneal dystrophies.

Conclusions : Using exome chip, we identified rare variants for refractive error in 43 novel genes. Further validation studies are necessary to evaluate their role in refractive error development.

This is a 2021 ARVO Annual Meeting abstract.