A study led by an international coalition of researchers, and published in JAMA Ophthalmology, evaluated the genetic risk factors for central serous chorioretinopathy (CSCR) and assessed the potential for genetic overlap with age-related macular degeneration (AMD).
Give me some background.
For this research, investigators used the results from two previous studies with genome-wide analysis studies (GWASs) on European and Japanese patients with chronic CSCR (cCSCR) and CSCR, respectively.
These studies identified three CSCR genetic risk loci (CFH, GATA5, and TNFRSF10A). Interestingly, two of these three loci (CFH and TNFRSF10A) were also associated with AMD.
Talk about the study.
In this three-cohort genetic association study, investigators conducted a meta-analysis of the GWASs from two national biobanks, FinnGen and Estonian Biobank (EstBB), as well as from the aforementioned study on European cCSCR patients.
Overall, 1,176 CSCR patients and 526,787 controls were included in the meta-analysis.
What did they assess?
Researchers assessed gene expression using cultured choroidal endothelial cells and public ocular single-cell ribonucleic acid (RNA) sequencing data sets to replicate the two known CSCR genetic loci (CFH and GATA5) and report on three novel loci associated with CSCR.
Results?
They identified six genetic risk loci (CFH, CD34, CD46, NOTCH4, PREX1, and LAMA5) that were particularly expressed in choroidal vascular endothelial cells in comparison to the retina and retinal pigment epithelium (RPE).
What did that tell them?
These findings confirmed the role of choroidal vascular dysfunction in CSCR pathogenesis.
Anything else?
Additionally, the loci NOTCH4 and CD34/46 were found to have potential links to both vascular and immune function.
Together with CFH, these three loci suggest that genetic variation in the complement cascade may be associated with CSCR.
Tell me more.
Of note, three of the six total-reported loci variants were also associated with AMD, but the direction of effect is opposite in CFH and NOTCH4 and concordant in the TNFRSF10A locus.
Limitations?
In the FinnGen and EstBB cohorts, CSCR patients were identified using the International Classification of Disease (ICD-10) code H35.7, as the review of medical records or imaging was not available.
Also, this study used cohorts predominantly made up of patients of European descent. Further studies on a more diverse group of patients are needed to generalize the results.
Significance?
By identifying the six genetic risk loci for CSCR, researchers outlined the role of genes in choroidal vascular function and complement regulation for CSCR pathogenesis.
Further, these results suggest that polygenic AMD risk is associated with a reduced risk of CSCR, and this genetic overlap is largely due to loci with complement genes.