Genome-wide association study underlines the role of the complement system in chronic central serous chorioretinopathy

Abstract

Purpose : Central serous chorioretinopathy (CSC) is characterized by subretinal fluid accumulation between the neuroretina and the retinal pigment epithelium (RPE) and its etiology is currently unknown. Genetic studies on cCSC are limited to candidate gene approaches; no unbiased genome-wide association studies (GWAS) have yet been reported for cCSC. In this study, we performed a GWAS in order to discover genetic loci associated with chronic CSC (cCSC) and to better understand the etiology of the disease.

Methods : We performed a GWAS using 521 cCSC patients and 3577 population controls using the Firth-bias corrected likelihood test corrected for sex and two principal components. Additionally, haplotypes at the complement factor H (CFH) locus were analyzed and pathway analyses with MAGMA and VEGAS2 were performed. The effect of genetic variants on gene expression was evaluated with PrediXcan, using publicly available expression data of GTEx.

Results : One locus on chromosome 1 at the complement factor H (CFH) gene reached genome-wide significance and was associated with an increased risk of cCSC (P=3.12x10^-11, odds ratio (OR) = 1.57). The CFH haplotypes H1 and H3 were protective for cCSC, whereas haplotypes H2, H4, H5 and the aggregate of rare CFH haplotypes conferred increased risk. Pathway analyses showed a significant involvement of the complement cascade and ARF pathway in cCSC. Using PrediXcan, we identified significant changes in predicted expression of multiple complement genes located in the CFH locus, namely CFH, complement factor H related 1 (CFHR1) and complement factor related 4 (CFHR4). Additionally, novel associations with another complement regulator, a potassium channel and a tumor necrosis factor were identified.

Conclusions : In this study, we identified a locus on chromosome 1 at the CFH gene that is strongly associated with cCSC, and we report novel protective and risk-conferring haplotypes in this gene. Pathway analyses and gene expression analysis showed enrichment of complement related pathways. Taken together, this study underscores the importance of the complement pathway in cCSC and provides new candidate genes that may be implicated in the etiology of cCSC.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.