Androgenic alopecia (AGA or Male Pattern Baldness) is a heritable condition affecting up to 80% of European men. The cause of Androgenic Alopecia is DHT binding to the androgen receptors in the scalp and causing the miniaturisation and eventual death of the hair follicle.

While a variety of genes have been implicated in AGA/MPHL, some of the most significant include:

• Androgen receptor gene (AR): Located on the X chromosome, this gene is strongly associated with AGA/MPHL due to the androgen-dependent nature of the condition. Notably, the AR locus exhibits multiple distinct signals. Despite its strong association, the exact causal variant and the role of the neighboring EDA2R gene remain unclear.
  • In a study titled ‘Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia’ , It was found that Androgen receptor content in female frontal hair follicles was approximately 40% lower than in male frontal hair follicles. Cytochrome P-450-aromatase content was 6 times higher in women then men. AND Frontal hair follicles in women had 3 and 3.5 times less 5alpha-reductase type I and II, respectively, than frontal hair follicles in men.
  • This confirms what we’ve all known for a long time. The reason why women tend to suffer at lower rates and less severely from androgenic alopecia is because, they have less androgen receptor density in the scalp, most aromatase in the scalp, and less androgens in the scalp particularly the potent androgen DHT which is produced through the 5 alpha reductase pathways.
• Steroid-5-α-reductase type II (SRD5A2): This gene encodes an enzyme responsible for converting testosterone to dihydrotestosterone (DHT). SRD5A2 is currently the only known therapeutic target for AGA/MPHL.
  • Interestingly one study found that the 5alpha-reductase type 1, but not type 2, gene is expressed in anagen hairs plucked from the vertex area of the scalp of hirsute women. However this may not be the same for men with androgenetic alopecia. 
  • In a study titled ‘mRNA Levels of Aromatase, 5α-Reductase Isozymes, and Prostate Cancer-Related Genes in Plucked Hair from Young Men with Androgenic Alopecia’ the type 2 5 alpha reductase isoenzyme was most associated with androgenic alopecia, as this isoenzyme MRNA levels were significantly higher in AGA groups then control groups. From this we can delicately assume a more targeted approach to inhibiting the type 2 5 alpha reductase isoenzyme would be most effective at halting androgenic alopecia. 
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  • The researchers noted that the type 1 and 3 5 alpha reductase isoenzyme did not reach statistical significance, but had a much wider variance, indicating their presence may have an individual effect. Speculatively, this might be why individuals who failed to achieve results on Finasteride, often find success on Dutasteride, as Dutasteride may target unaddressed levels of these isoenzymes
• Wnt Family Member 10A (WNT10A): Located on chromosome 2q35, this gene is a known regulator of hair cycling. Studies have shown that a specific risk allele at this locus results in decreased WNT10A expression, impacting hair follicle cycling.
  • Other genes associated with AGA and this pathway are WNT3, LGR4, RSPO2, SOX13, DKK2, TWIST1, TWIST2, IQGAP1, and PRKD1
• Apoptosis pathway: Apoptosis, or programmed cell death, plays a role in the hair growth cycle. MPB is characterized by a shorter anagen phase, potentially linked to increased apoptosis in hair follicle cells. Genes in this pathway associated with MPB include BCL2, DFFA, TOP1, IRF4, and MAPT.
• Fibroblast growth factor 5 (FGF5): This gene is known to regulate hair growth.
• Interferon regulatory factor 4 (IRF4): This gene has been previously linked to hair pigmentation.
• Early B cell factor 1 (EBF1): This gene, located on chromosome 5q33.3, encodes a transcriptional regulator and may interact with WNT10A in AGA/MPHL pathogenesis.
• Other genes in the WNT and androgen signaling pathways: These include DKK2, FZD10, FAM53B, TOP1, FAM9B, HDAC4, and HDAC9.

In addition to those listed above, a TWAS (transcriptome-wide association study) identified several other potentially relevant genes:

• CD59: This gene is involved in the immune response and could be related to inflammation in hair follicles.
• ZDHHC5: This gene is involved in cell adhesion, which is important for hair follicle function.
• CHD6 and ZIC2: Both of these genes are involved in transcriptional regulation. ZIC2 specifically might be significant due to its role in inhibiting the Wnt/β-catenin signaling pathway, which is implicated in AGA/MPHL.
• ADAMTS18: This gene encodes a protein with proteolytic function. Abnormal proteolytic activity could disrupt the balance of hair shedding and replacement.
• ATP6V0D1: This gene encodes a component of vacuolar ATPase, which is involved in cellular energy production. ATP-related processes are important for hair follicle function, and the current treatment minoxidil targets these processes.
• TMEM178B: This gene encodes a transmembrane protein and might play a role in transporting steroid hormones, including androgens.

A 2023 review article states that GWAS has identified 389 risk loci for AGA/MPHL. The article notes that these loci collectively explain approximately 39% of the observed phenotypic variance in MPHL, as determined in a 2018 population-based GWAS.

A 2017 GWAS reports the identification of 71 independently replicated loci for AGA/MPHL. This study concluded that these loci explain 38% of the heritability of MPB.

For those who dont know

• Heritability refers to the proportion of variation in a trait within a population that can be attributed to genetic differences among individuals.
• Phenotypic variance describes the degree to which individuals in a population differ for a particular trait.

Therefore, the two sources and the concepts of heritability and phenotypic variance suggest that the identified loci account for approximately 38-39% of the differences observed in MPB within a population. 

What is the significance of all of this?

• Identifying Druggable Targets: Several MPHL-associated genes encode proteins that could be targeted by drugs. The sources point out that 45 candidate genes identified through GWAS were considered druggable targets, suggesting promising avenues for therapeutic development. This will help develop precision medicine, which could lead to more effective treatments with fewer side effects
• Understanding Mechanisms: We understand the basics of androgenic alopecia however there are a lot of mysteries in this process. Further Genome Wide Association studies will help develop treatments that address specific pathways, such as WNT signaling, apoptosis, or inflammation, beyond simply targeting androgen signaling. GT20029 is as far as I can tell the most targeted treatment for Androgenic Alopecia we’ve seen.
• Drug Repurposing: Existing drugs initially developed for other conditions could potentially be repurposed for MPHL treatment if their mechanisms of action overlap with relevant pathways. The sources specifically mention curcumin, a natural compound with anti-inflammatory properties, and succinic acid, involved in cellular energy production, as potential candidates based on their connections to MPHL-associated genes

Refrences:

 Sawaya ME, Price VH. Different levels of 5alpha-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol. 1997 Sep;109(3):296-300. doi: 10.1111/1523-1747.ep12335779. PMID: 9284093.

https://www.scielo.br/j/bjmbr/a/PBp7XhpJHQSrkqYxvczfY4Q/?lang=en

Sánchez, P.; Serrano Falcón, C.; Martínez Rodríguez, S.; Torres, J.M.; Serrano, S.; Ortega, E. mRNA Levels of Aromatase, 5α-Reductase Isozymes, and Prostate Cancer-Related Genes in Plucked Hair from Young Men with Androgenic Alopecia. Int. J. Mol. Sci. 2023, 24, 17461. https://doi.org/10.3390/ijms242417461

Henne SK, Nöthen MM, Heilmann-Heimbach S. Male-pattern hair loss: Comprehensive identification of the associated genes as a basis for understanding pathophysiology. Med Genet. 2023 Apr 5;35(1):3-14. doi: 10.1515/medgen-2023-2003. PMID: 38835416; PMCID: PMC10842561.

Pirastu, N., Joshi, P.K., de Vries, P.S. et al. GWAS for male-pattern baldness identifies 71 susceptibility loci explaining 38% of the risk. Nat Commun 8, 1584 (2017). https://doi.org/10.1038/s41467-017-01490-8