Light processing and regulators are important mechanisms in refractive error

Abstract

Purpose : Myopia is a major cause of blindness worldwide. The underlying pathways remain largely unknown. Recently, a large GWAS meta-analysis on refractive error (RE) of CREAM and 23andMe(N=160,420) yielded 152 loci. The next step is to clarify biological pathways including the role of regulatory elements.

Methods : We used summary statistics of the aforementioned GWAS meta-analysis, and performed a gene set enrichment analysis on single-nucleotide polymorphisms (SNPs) with a P-value ≤ 1,00E-05 using DEPICT. Pearson correlation coefficients (r) were calculated between gene sets to form pathway families (i.e. gene set clusters with r > 0.4). To search for regulatory elements, we combined the VISTA enhancer database based on activity experiments conducted in transgenic mice, with POSSUM, a hereditary dysmorphology database based on human data using data mining software Spotfire on the 152 tag SNPs.

Results : Firstly, 66 gene sets were significantly associated with RE with a false discovery rate < 5% and a P-value < 0.05. 55 (83%) gene sets were eye-related. The most significant gene set was the abnormal photoreceptor inner segment morphology (P-value 1.79E-07). The eye-related gene sets consisted of specific pathway families: the retinal outer nuclear layer (n=27; 55%), the detection of light stimulus (n=13; 24%) , non-motile cilium (n=3; 5%) and anterior eye segment (n=3; 5%). The correlation between the detection of light stimulus, retinal outer nuclear layer and non-motile cilium pathway families were > 0,6 [range r 0,61 – 0,68]. Secondly, 7 SNPs were located in enhancer regions which play a role in eye-development. 2 of these SNPs were specifically related to myopia, and are known to be human non-coding fragments with gene enhancer activity.

Conclusions : Our study strongly supports the importance of light processing as a primary role for the development of RE, and suggests that regulatory elements are major players in this process.

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