Shared Genetic Architecture Between Psychiatric Disorders and Keratoconus: Insights From a Large-Scale Genome-Wide Cross-Trait Analysis

Purpose: The correlation between keratoconus (KC) and psychiatric disorders has been reported, but whether there is a genetic correlation between the 2 remains unclear. Methods: We identified genetic overlaps between KC and 6 psychiatric disorders by using comprehensive summary data from genome-wide association studies. Cross-trait pleiotropic analysis uncovered shared loci and genes, whereas functional annotations and tissue-specific investigations assessed the impact of these pleiotropic genes. Finally, bidirectional Mendelian randomization was applied to explore causal relationships. Results: Significant genetic correlation and genetic overlap were observed in 3 of the 6 trait pairs. A multiplicity study using the composite null hypothesis discovered significant possible multiplicity single nucleotide variants across 3 trait pairs, revealing 13 pleiotropic genetic loci, of which 3 were confirmed as colocalized loci with a posterior probability (PP.H4) exceeding 0.75. Significantly, numerous pleiotropic loci were identified across various paired traits, including 11p15.5 and 9q34.3. At the gene level, 137 pleiotropic genes were identified, including PDDC1 , PIDD , and PNPLA2 . Gene-based analyses indicated that these genes were significantly enriched in the brain and fibroblasts. Pathway analysis highlighted critical roles in Wnt/β-catenin signaling pathway. Mendelian randomization analysis further analyzed the correlation between these diseases. Conclusions: This study offers additional evidence of a multifaceted relationship between psychiatric disorders, specifically attention-deficit/hyperactivity disorder, anorexia nervosa, and posttraumatic stress disorder, and KC. At the same time, it may facilitate novel medications and enhanced clinical treatment techniques.