Neuroimmune Genetic Overlap Between Chronic Pruritic Skin Diseases and Major Depressive Disorder: Insights from Cross-Trait GWAS Analysis.

BACKGROUND

Psoriasis (PSO), atopic dermatitis (AD), and urticaria (URT) are chronic inflammatory skin diseases marked by severe pruritus. These conditions are frequently comorbid with psychiatric disorders, especially major depressive disorder (MDD). Despite this clinical overlap, the underlying shared genetic mechanisms driving these comorbidities remain largely unclear.

METHODS

We integrated large-scale European-ancestry genome-wide association study (GWAS) summary statistics for PSO, AD, URT, and MDD. Genetic overlap was assessed using linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), MAGMA-based gene and pathway analyses, PLACO cross-trait pleiotropy analysis, Bayesian colocalization, and summary-data-based Mendelian randomization (SMR). Tissue-specific enrichment and gene expression analyses were performed using GTEx transcriptomic resources.

RESULTS

All three skin diseases showed significant positive genetic correlations with MDD. We identified 70 genome-wide significant pleiotropic SNPs and 13 shared genomic risk loci across the pairwise IAD-MDD analyses, with 11q13.1 and 11q12.2 prominent in AD-MDD. Prioritized genes, including FADS1, SLC22A4, SLC22A5, and FOXP3, showed enrichment in immune-related tissues and brain regions. Functional analyses implicated transcriptional regulation, synaptic signaling, and IgE isotype switching, supporting shared immunological and neurobiological pathways.

CONCLUSION

This study provides genetic evidence consistent with shared susceptibility between pruritic inflammatory skin diseases and MDD. The findings generate hypotheses about immune-neural pathways underlying skin-psychiatric comorbidity, but they should be interpreted in light of key limitations, including European-only summary statistics, summary-level inference, possible sample overlap, and the absence of an independent replication cohort.