Rethinking Acne Pathogenesis with a New Genetic Framework

For decades, the underlying biology of acne has been framed largely around excess sebum, bacterial overgrowth, and inflammation. But a recent comprehensive genetics review challenges that familiar narrative.

By integrating evidence from rare monogenic disorders, family and twin studies, genome-wide association studies (GWAS), and emerging epigenetic data, the author argues that acne is fundamentally a disorder of sebaceous progenitor cell fate, migration, and tissue remodeling.

The “Comedo Switch Hypothesis”
Traditional models propose that puberty-associated androgen increases stimulate sebum production, leading to follicular blockage and secondary inflammation driven by Cutibacterium acnes. However, this framework fails to explain several clinical observations, including sebaceous gland atrophy within comedones and the effectiveness of retinoids, which lack direct antibacterial activity.

Genetic insights instead support the “comedo switch hypothesis,” in which sebaceous progenitor cells, located at the junctional zone of the hair follicle, adopt an inappropriate differentiation pathway.

Central to this process is Wnt signaling, a pathway that governs stem and progenitor cell identity. Stronger Wnt signaling biases progenitors toward an epidermal lineage, predisposing to comedone formation. That’s why retinoids may exert benefit as they antagonize Wnt signaling and restore appropriate differentiation cues.

Lessons from Rare Monogenic Disorders
Several rare genetic syndromes characterized by severe acne offer mechanistic clarity as well.

Gain-of-function variants in FGFR2 (as seen in Apert syndrome) disrupt fibroblast growth factor signaling and are strongly associated with comedonic acne that responds well to retinoids. Similarly, somatic NEK9 mutations in nevus comedonicus interfere with mitotic spindle orientation, highlighting the importance of directional cell division. Other syndromes, such as Frank–Ter Haar and Winchester syndromes, implicate defective extracellular matrix remodeling and impaired cellular migration.

These conditions reinforce the idea that progenitor cells must not only differentiate correctly, but also migrate to the appropriate follicular compartment to maintain sebaceous gland homeostasis. Failure of this migration results in the “intermediate” cell phenotype characteristic of comedones.

Genome-Wide Association Studies
Family and twin studies estimate that approximately 80% of acne risk is heritable. This observation is echoed in GWAS, which consistently show that genetic associations are strongest for severe acne phenotypes.

Across multiple large cohorts—some exceeding 20,000 cases—risk loci repeatedly converge on pathways governing Wnt signaling, cell adhesion, cellular motility, and tissue remodeling. Notably, early GWAS identified WNT10A, LGR6, OVOL1, and FST, while more recent studies added genes involved in integrin signaling, cytoskeletal dynamics, and lipid metabolism, including FASN and FADS1/2.

It’s also important to know that most GWAS signals show little direct connection to innate inflammation, suggesting that inflammation is a downstream epiphenomenon rather than a primary driver of disease.

Inflammation, Epigenetics, and Emerging Nuance
While genetics deemphasize inflammation as an initiating factor, epigenetic studies introduce nuance. DNA methylation analyses in skin and blood samples from patients with severe acne implicate immune pathways involving T cells, macrophages, and cytokine signaling, including IL1R1 and IL36RN.

These findings align with histologic evidence of early T-cell infiltration around comedones and suggest that immune activation amplifies—rather than initiates—disease.

Implications for Future Therapy
This genetic research reframes acne as a disorder of stem and progenitor cell regulation, opening the door to targeted, non-antibiotic, and non-retinoid interventions. Emerging therapeutic strategies, including inhibitors of fatty acid metabolism and advanced skin organoid models, aim to correct early pathogenic events before inflammation and scarring occur. And with the rapid progress of acne genetics over the past decade, preventive and mechanism-based therapies may finally be within reach.

Reference:

Van Steensel MAM. The Genetics of Acne. Ann Hum Genet. 2025;89(5):333-341. doi:10.1111/ahg.70014