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

Abstract

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 (SMR), colocalization, two-sample MR (TSMR), transcriptome-wide (TWAS) and proteome-wide (PWAS) 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), eQTL datasets from blood, skin-related tissues, and fibroblasts, along with six pQTL databases and a blood mQTL dataset. SMR and sensitivity analyses identified 16 candidate genes, refined to 9 by TWAS. Protein-level SMR and PWAS further recognized two plasma proteins (CRELD2 and TIMP4), with CRELD2 also supported by gene-level associations. A total of 10 non-redundant targets were functionally analyzed, revealing pathways beyond molecular transport, such as carnitine metabolism. Moreover, methylation regulated key genes, and immune cell-specific loci overlapped with acne risk. Transcriptomic data confirmed differential expression of several targets in acne lesions. Finally, we prioritized acne drug targets based on 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.