Towards the identification of causal genes for age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of visual impairment in ageing populations and has no radical treatment or prevention. Although genome-wide association studies (GWAS) have identified many susceptibility loci for AMD, the underlying causal genes remain elusive. Here, we prioritized nine putative causal genes by integrating expression quantitative trait locus (eQTL) data from blood (n = 2,765) with AMD GWAS data (16,144 cases vs. 17,832 controls) and replicated six of them using retina eQTL data (n = 523). Of the six genes, altering expression of cnn2, sarm1 and bloc1s1 led to ocular phenotype, impaired vision and retinal pigment epithelium (RPE) loss in zebrafish. Essential photoreceptor and RPE genes were downregulated in cnn2- and sarm1-knockdown zebrafishes. Through integration of GWAS and eQTL data followed by functional validation, our study reveals potential roles of CNN2, SARM1 and BLOC1S1 in AMD pathogenesis and demonstrates an efficient platform to prioritise causal genes for human complex diseases.