Genome-wide association and multi-omics analyses provide insights into the disease mechanisms of central serous chorioretinopathy

Abstract

Central serous chorioretinopathy (CSC) is a major cause of vision loss, especially in middle-aged men, and its chronic subtype can lead to legal blindness. Despite its clinical importance, the underlying mechanisms of CSC need further clarification. In this study, we conducted a meta-analysis of three genome-wide association studies (GWASs) for CSC consisting of 8811 Asians and Caucasians, followed by replication in an additional 4338 Asians. We identified four genome-wide hits, including a novel hit (rs12960630 at LINC01924-CDH7, P_meta = 2.97 × 10^-9). A phenome-wide association study for rs12960630 showed a positive correlation between its CSC risk allele with plasma cortisol concentration. Expression/splicing quantitative trait loci (QTL) analyses showed an association of all these hits with the expression and/or splicing of genes in genital organs, which may explain the sex differences in CSC. Protein QTL also suggested the protein-level contribution of the complement factor H pathway to CSC pathogenesis.

Fig. 1

Manhattan plots of the discovery stage of the genome-wide meta-analysis for central serous chorioretinopathy (CSC). The plots represent the − log₁₀ transformed P-values for all single nucleotide polymorphisms. The red and blue horizontal lines represent the genome-wide significant threshold (P = 5.0 × 10^–8) and the suggestive threshold (P = 5.0 × 10^–7), respectively. Seven loci (arrows), including previously reported susceptibility loci for CSC (CFH, TNFRSF10A-TNFRSF10A-DT, and near GATA5) associate with CSC genome-wide significantly, and six loci (arrowheads) associate with CSC suggestively.