An Insertion Variant in CRH Confers an Increased Risk of Central Serous Chorioretinopathy

PURPOSE: To identify a novel corticotropin-releasing hormone (CRH) gene variant relevant in patients with central serous chorioretinopathy (CSC). METHODS: We performed a genetic study of CSC in families and sporadic cases with controls. Using whole-exome sequencing and linkage analysis, we identified a heterozygous insertion variant, Gln52insPro, in the CRH gene that cosegregated in two Chinese families with CSC. This variant was evaluated among an additional 1307 patients with CSC and 1438 ethnicity-matched control individuals from three independent Chinese cohorts. RESULTS: The CRH variant was strongly associated with CSC in these cohorts of Chinese patients (P(meta) = 1.24 × 10(−11); odds ratio, 3.01; 95% confidence interval, 2.15–4.21). The risk variant Gln52insPro decreased CRH gene expression. CONCLUSIONS: Our results implicate the hypothalamic–pituitary–adrenal stress response system in the pathogenesis of CSC and provide a novel rationale for therapeutic intervention.