Shared genetic risk locus for central serous chorioretinopathy and varicose veins

Abstract

Purpose : In a prior genome-wide association study (GWAS) meta-analysis for central serous choroidopathy (CSC), we noted a nominally significant rare variant (P = 8.4e-07) that stood out because of a potential genetic risk overlap with varicose veins. Here, we interrogate this variant in a larger sample (over double the size) for central serous chorioretinopathy to test for definitive evidence of association to both CSC and varicose veins, thus underscoring the mechanistic theory of CSC as a venous overload choroidopathy.

Methods : We first conducted a larger genome-wide association study of CSC including 1,477 patients and 455,449 controls identified using ICD-10 codes from the FinnGen study. These results confirmed a strong association of the rare variant rs113791087 (minor allele frequency = 0.5%) on chromosome 12. Rrs113791087 was the lead variant in the region and lacked convincing nearby tag SNPs. We conducted directed replication in participants of European ancestry in the Million Veteran Program (MVP; 706 ICD-based cases and 273,198 controls) and AllOfUs cohorts (128 ICD-based cases and 114,069 controls), as well as a previously published European dataset of patients with chronic CSC (521 patients and 3,577 controls).

Results : In the discovery cohort, the lead variant rs113791087 was associated with an almost 3-fold increase in the risk of CSC (OR = 2.85; P = 4.5e-9). The effect size was robust to the exclusion of cases and controls with 37 ICD codes reflecting potential confounding causes of fluid maculopathy (OR = 3.15, P = 1.8e-6). Rs113791087 was significantly associated with CSC in all replication cohorts (ORs = 2.21–8.00, P = 0.02–3.0e-9) (Table 1) and a cross-cohort meta-analysis including 2,452 cases and 881,210 controls (OR = 3.06, P = 7.4e-15). In a phenome-wide association study of 2,469 diverse traits in FinnGen, rs113791087 was most significantly associated with varicose veins (38,467 cases and 432,223 controls; OR = 1.39; P = 3.1e-10), and this association replicated in a single-variant analysis of varicose veins in the UK Biobank (OR = 1.22, P = 6.2e-3).

Conclusions : We identify a novel genetic locus with an unusually high odds ratio linking CSC and varicose veins, supporting CSC as a venous overload choroidopathy.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Rs113791087 and risk of central serous chorioretinopathy in different study populations