Multi-Omics Analysis Identifies Genetic Mechanisms and Therapeutic Targets for Acne Vulgaris.

Acne vulgaris is a chronic inflammatory disorder with complex pathophysiology. However, challenges such as antibiotic resistance, side effects, and recurrence highlight the need for precision therapies. This study employed a multi-omics approach, integrating summary-data-based Mendelian randomization, colocalization, two-sample Mendelian randomization, transcriptome-wide association studies, proteome-wide association studies, and functional analyses to identify acne-associated genes and proteins. We analyzed acne GWAS data (n_cases = 34,422; n_controls = 364,991); expression quantitative trait loci datasets from blood, skin-related tissues, and fibroblasts; 6 protein quantitative trait loci databases in plasma; and a blood methylation quantitative trait loci dataset. Summary-data-based Mendelian randomization and sensitivity analyses identified 16 candidate genes, refined to 9 by transcriptome-wide association studies. Protein-level summary-data-based Mendelian randomization and proteome-wide association studies further recognized 2 plasma proteins (CRELD2 and TIMP4), with CRELD2 also supported by gene-level associations. A total of 10 nonredundant targets were functionally analyzed, revealing pathways beyond molecular transport, such as carnitine metabolism. Moreover, key genes regulated by methylation and immune-cell-specific loci showed significant overlap with acne risk loci. Transcriptomic data confirmed differential expression of several targets in acne lesions. Finally, we prioritized acne drug targets on the basis of our results and their druggability, highlighting SLC22A5 activators and CRELD2 inhibitors as promising Tier 1 candidates. These findings advance the molecular understanding of acne pathogenesis and suggest potential therapeutic targets.