Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Abstract

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants, increased the established independent signals from 37 to 161 and revealed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and functional contributions to refractive error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes elicited novel mechanisms such as rod and cone bipolar synaptic neurotransmission, anterior segment morphology, and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade, and delineate potential pathobiological molecular drivers.