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.