Role of the Complement System in Chronic Central Serous Chorioretinopathy: A Genome-Wide Association Study

Importance To date, several targeted genetic studies on chronic central serous chorioretinopathy (cCSC) have been performed; however, unbiased genome-wide studies into the genetics of cCSC have not been reported. To discover new genetic loci associated with cCSC and to better understand the causative mechanism of this disease, we performed a genome-wide association study (GWAS) on patients with cCSC. Objective To discover new genetic loci and pathways associated with cCSC and to predict the association of genetic variants with gene expression in patients with cCSC. Design, Setting, and Participants This case-control GWAS was completed in the general community, 3 referral university medical centers, and outpatient care on Europeans individuals with cCSC and population-based control participants. Genotype data was collected from May 2013 to August 2017, and data analysis occurred from August 2017 to November 2017. Main Outcomes and Measures Associations of single-nucleotide polymorphisms, haplotypes, genetic pathways, and predicted gene expression with cCSC. Results A total of 521 patients with cCSC (median age, 51 years; interquartile range [IQR], 44-59 years; 420 [80.6%] male) and 3577 European population-based control participants (median age, 52 years; IQR, 37-71 years; 1630 [45.6%] male) were included. 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 (rs1329428; odds ratio [OR], 1.57 [95% CI, 1.38-1.80]; P = 3.12 × 10−11). The CFH haplotypes H1 and H3 were protective for cCSC (H1: OR, 0.64 [95% CI, 0.53-0.77]; P = 2.18 × 10−6; H3: OR, 0.54 [95% CI, 0.42-0.70]; P = 2.49 × 10−6), whereas haplotypes H2, H4, H5, and the aggregate of rare CFH haplotypes conferred increased risk (H2: OR, 1.57 [95% CI, 1.30-1.89]; P = 2.18 × 10−6; H4: OR, 1.43 [95% CI, 1.13-1.80]; P = 2.49 × 10−3; H5: OR, 1.80 [95% CI, 1.36-2.39]; P = 4.61 × 10−5; rare haplotypes: OR, 1.99 [95% CI, 1.43-2.77]; P = 4.59 × 10−5). Pathway analyses showed involvement of the complement cascade and alternative open reading frame (ARF) pathway in cCSC. Using PrediXcan, we identified changes in predicted expression of complement genes CFH, complement factor H related 1 (CFHR1), complement factor related 4 (CFHR4), and membrane cofactor protein (MCP/CD46). Additionally, the potassium sodium-activated channel subfamily T member 2 (KCNT2) and tumor necrosis factor receptor superfamily member 10a (TNFRSF10A) genes were differentially expressed in patients with cCSC. Conclusions and Relevance In this GWAS on cCSC, we identified a locus on chromosome 1 at the CFH gene that was significantly associated with cCSC, and we report protective and risk-conferring haplotypes in this gene. Pathway analyses were enriched for complement genes, and gene expression analysis suggests a role for CFH, CFHR1, CFHR4, CD46, KCNT2, and TNFRSF10A in the disease. Taken together, these results underscore the potential importance of the complement pathway in the causative mechanisms of cCSC.