Abstract
OBJECTIVE: Psychiatric disorders are frequently comorbid with ocular diseases, yet the shared genetic basis and potential causal links remain unclear. This study aimed to systematically investigate the shared genetic architecture, bidirectional causality, and implicated biological pathways between common psychiatric disorders and ocular diseases. METHODS: We analyzed four psychiatric disorders and eight ocular diseases using an integrative genome-wide analytical framework. We used linkage disequilibrium score regression (LDSC) to estimate genome-wide genetic correlations and local genetic correlation analysis (LAVA) to identify region-specific shared signals. Bidirectional Mendelian randomization (MR) was performed to assess causal relationships. Shared loci were identified using conditional/conjunctive false discovery rate (cond/conjFDR) and evaluated by colocalization. Variants were then annotated and mapped to genes using FUMA, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction (PPI) network analyses to prioritize pathways and hub genes. RESULTS: LDSC revealed significant genetic correlations between anxiety disorder and conjunctivitis, and between major depressive disorder (MDD) and several ocular diseases, including cataract, conjunctivitis, and keratitis. LAVA further confirmed shared, directionally consistent local genetic effects between MDD and these ocular phenotypes across multiple genomic regions. Bidirectional MR suggested that MDD increases the risk of cataract, conjunctivitis, and keratitis, with evidence for bidirectional causality between cataract and MDD. The conjFDR analysis (conjFDR < 0.05) identified approximately 70 independent shared loci (lead SNPs). Functional annotation prioritized representative SNPs with potential functional and regulatory evidence, including rs1029871 and rs678 for bipolar disorder-cataract, rs1042602 for MDD-cataract, and rs12185233 and rs17651549 shared between schizophrenia and both cataract and conjunctivitis. Enrichment analyses of mapped genes suggested that pathways related to hyaluronic acid and amino acid metabolism, cholinergic signaling, and immune-inflammatory processes may contribute to the comorbidity between psychiatric and ocular diseases. CONCLUSION: This genome-wide study reveals genetic links between psychiatric and ocular diseases and provides evidence for bidirectional causality in selected phenotypes. Metabolism-inflammation-related pathways may contribute to comorbidity along the eye-brain axis, offering leads for future mechanistic validation.