Exome-focused Rare and Common Variant Analyses of Ocular Traits in a Sardinian Cohort

Abstract

Purpose : Genomewide association studies (GWAS) have concentrated on analyzing common variants in the search for risk genes in complex traits. Low frequency SNPs are filtered out during quality control because of potential for distortion of commonly used test statistics and subsequent inflation of type I error. Newer genotyping arrays and comprehensive sequencing efforts have meant several methods have been developed for analysis of rarer variants. Here we use standard GWAS methods for common variation, and compare four methods for analyzing SNPs with minor allele frequencies below 5% to an exome-focused association study of intra-ocular pressure, corneal curvature radius, central corneal thickness and anterior chamber depth.

Methods : 2330 individuals from the Ogliastra Genetic Park cohort were genotyped on the Illumina ExomePlus array. For common variation we used a mixed-model based association test (EMMAX) which models underlying relationships in the cohort. For rare variants we compared four classes of test using tools that can account for kinship; probabilistic search tool (Variant Annotation, Analysis and Search Tool (VAAST2)), burden test (Kernel-Based Adaptive Cluster (KBAC)), variance components test (Sequence Kernel Association Test (SKAT)) and combined test (Mixed-effects Score Test (MiST)).

Results : Suggestively significant results in common variant analyses were found in rs9217 on chromosome 17 for intraocular pressure (p=4.65x10-7) in the ZBTB4 gene, rs12711521 on chromosome 1 in the MASP2 gene and rs121908120 on chromosome 2 in the WNT10A gene for central corneal thickness. No variants reached suggestive significance for corneal curvature radius or anterior chamber depth. Rare variant analyses are ongoing and will be compared with common variant analyses when complete.

Conclusions : As the paradigm for analyzing genetic data has shifted from genotyping to sequencing, many analysis options exist depending on data structure and variant frequency. We analyzed rare and common variants in a range of ocular traits using methods that leverage different approaches to the data. This allows rare alleles to be analyzed without increasing type I error and also takes account of directionality of effect. Combining rare and common variant analyses will be a valuable approach to many complex eye disorders, where much missing heritability remains.

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