Integrative Transcriptome- and Proteome-Wide Analyses Prioritize Candidate Genes for Eczema Susceptibility

Eczema is a common inflammatory skin disease. Although genome-wide association studies (GWAS) have identified multiple eczema susceptibility loci, the underlying effector genes and molecular contexts remain incompletely resolved. This study aimed to integrate transcriptomic and proteomic reference resources to prioritize candidate genes with cross-panel molecular support. Primary discovery combined cross-tissue transcriptome-wide association study (TWAS) using the sparse canonical correlation analysis-aggregated Cauchy association test (sCCA-ACAT) with single-tissue TWAS across 49 Genotype-Tissue Expression (GTEx) v8 tissues. Candidates were further evaluated using whole-blood and adipose TWAS, brain proteome-wide association study (PWAS), and exploratory PWAS with brain proteomic prediction weights derived separately from male and female reference samples. Summary-data-based Mendelian randomization (SMR), heterogeneity in dependent instruments (HEIDI) testing, and blood expression quantitative trait locus (eQTL) colocalization were used for genetic prioritization. Cross-tissue and single-tissue TWAS identified 50 and 164 genes, respectively, at a false discovery rate (FDR) < 0.05. Of the 35 overlapping genes, 16 were retained after conditional and joint analysis. Integration with peripheral TWAS and brain PWAS prioritized LIME1 and TRAF3. LIME1 showed significant but oppositely signed associations in whole-blood TWAS and brain PWAS, whereas TRAF3 showed support in adipose TWAS and brain PWAS, together with SMR and blood-eQTL colocalization support. PWAS using male-derived brain proteomic weights additionally identified ASTN2. Overall, TRAF3 showed the most complete evidence profile, whereas LIME1 remained a cross-panel candidate with discordant association directions. These analyses provide gene-prioritization evidence.