Integrative Multi-Omics Mendelian Randomization Identifies BLMH as a Keratinocyte-Enriched Protective Candidate Gene and Potential Therapeutic Target in Psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease driven by complex interactions between genetic susceptibility, immune dysregulation, and keratinocyte dysfunction. Although genome-wide association studies have identified numerous risk loci, most studies have focused on genetic associations rather than causal inference, limiting the identification of effective therapeutic targets. We employed an integrative multi-omics strategy to identify causal genes and potential therapeutic candidates for psoriasis. METHODS: We integrated psoriasis genome-wide association study (GWAS), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) datasets to perform two-sample Mendelian Randomization (MR) analyses and prioritize high-confidence causal genes. Most genetic datasets were derived from European-ancestry populations. Single-cell transcriptomic analysis was then used to determine their cell-type-specific expression patterns. Finally, drug-target prediction and molecular docking were applied to identify potential therapeutic compounds. RESULTS: Integrative MR analyses indicated that genetically predicted higher BLMH expression and plasma protein levels were significantly associated with reduced psoriasis risk, with colocalization analysis supporting shared causal variants at the BLMH locus. Single-cell transcriptomics further demonstrated keratinocyte-enriched expression of BLMH and marked downregulation in psoriatic lesional skin. Drug screening using DSigDB combined with molecular docking identified tamibarotene as a potential BLMH-binding compound with favorable docking affinity. In vitro experiments showed that tamibarotene treatment was associated with increased BLMH expression and reduced KRT16, IL6, and IL8 expression in the M5-stimulated HaCaT model. CONCLUSION: Our integrative multi-omics analysis nominates BLMH as a keratinocyte-enriched protective candidate gene in psoriasis and suggests tamibarotene as a potential repurposed compound for further investigation. However, the experimental validation remains preliminary, and further mechanistic, in vivo, and translational studies are required to validate these findings.