Genome Wide Pleiotropic Analysis Reveals Shared Genetic Architecture and Pathological Basis Between Retinitis Pigmentosa and Relevant Ocular Comorbidities.

PURPOSE: Retinitis pigmentosa (RP) is a leading cause of irreversible blindness in working-age populations and frequently cooccurs with multiple ocular disorders. As their shared genetic basis remains poorly understood, this study aimed to elucidate the shared genetic architecture underlying RP and relevant ocular comorbidities.

METHODS

Using large-scale genome-wide association data, we systematically investigated pleiotropy, genetic correlation, cell-type specificity, and genetically predicted causality between RP and major ophthalmic comorbidities.

RESULTS

We observed significant genetic correlations and pleiotropic enrichment between RP and retinal detachments and breaks (RDAB), retinal vascular occlusion (RVO), and age-related macular degeneration (AMD), with notable SNP-level overlap between RP and primary open-angle glaucoma (POAG). RP and RDAB, as well as AMD, shared genetic associations at chr1:196176201-197311241 and chr10:123900764-125869042. Totally, 41, 25, 114, and 397 pleiotropic loci were identified between RP and RDAB, RVO, POAG, and AMD, implicating pathways related to cell division, metabolic regulation, immune activation, and complement activation. A novel causal variant (rs36212731) and four pleiotropic genes (ARMS2, HTRA1, CFH, PLEKHA1) were discovered between RP and RDAB. Ten causal variants and 24 pleiotropic genes were identified between RP and AMD. MR analyses demonstrated a genetically causal effect of RP on an increased risk of RDAB and RVO (P˂0.05), and AMD was associated with an increased risk of RP. Cell-type enrichment analyses highlighted vascular smooth muscle cells and retinal pigment epithelium as key mediators of shared susceptibility between RP and RDAB, and POAG.

CONCLUSIONS

This study reveals robust genetic and potential causal links between RP and RDAB, RVO, as well as AMD, along with complex pleiotropic associations with glaucoma. These findings provide novel genetic insights into the shared pathogenic mechanisms and generate hypotheses for future biological, translational, and clinical research.