Medical Review by Dr. Luna, MD
Medical Director, Roots Hair Club
Why is AGA considered to be heritable?
The familial occurrence of AGA is well documented, and monozygotic twins display a striking phenotypic resemblance. To date, two twin studies of AGA have been performed. These generated heritability estimates of 0.81 [95% confidence interval (CI) 0.77–0.85] in early-onset AGA families (25–36 years) and 0.79 (95% CI 0.4–0.85) in elderly males (>70 years), respectively. However, the true heritability may even be higher, as any random misclassification of AGA severity, for example in studies involving self-assessment, would lead to an underestimation of the heritability. The issue of whether environmental factors – in some instances mediated through epigenetic mechanisms are involved in AGA remains unclear.1
The genetic involvement is pronounced, and the importance of genes concurs with marked racial differences in prevalence of AGA; non-Caucasians often exhibit significantly less balding. The genes for type 1 and type 2 five alpha reductase have been shown not to be associated with the inheritance of AGA3. Polymorphism of the AR gene is associated with male pattern baldness (4), however, the AR gene is located on the X chromosome and does not explain the relatively strong concordance of the degree of baldness in fathers and sons. No specific gene has been identified so far, though single gene mutations, such as abnormality of the AR, might be necessary, but not sufficient for the phenotype (4).
The following describes the current status of AGA genetic research and anticipated developments in the field (1)
- Familial occurrence of AGA is well documented.
- There are 12 genomic regions of interest.
- The strongest association signal is observed on the long arm of the X chromosome (AR/EDA2R-locus). The remaining risk loci are located on the autosomes (chromosomes 1, 2, 3, 5, 7, 12, 17, 18 and 20
- The strongest finding on the autosomes is for the intergenic region between paired box 1 (PAX1) and forkhead box A2 (FOXA2) on chromosome 20
- Chromosome 2 and 7: Histone deacetylase class II molecules, that is HDAC4 on chromosome 2q37 and HDAC9 on chromosome 7p21.1 Both HDAC4 and HDAC9 have been found to be expressed in human hair follicle known to act as transcriptional repressors via the deacetylation of histone proteins and nuclear compaction of the chromatin. Research has shown that both HDACs play a role in the regulation of AR signaling via direct or indirect interaction with the AR protein. Thus, both may contribute to the AGA-specific androgen-induced miniaturization of hair follicles. The above-mentioned AGA risk loci also contain two members of the TWIST basic helix–loop–helix (bHLH) transcription factors family, that is TWIST2 (2q37) and TWIST1 (7p21.1) TWIST1 is implicated in hair cycle regulation, where it plays a crucial role in the control of anagen-to-catagen transition. Twist gene, TWIST2, has been implicated in the development of mesenchymal cell lineages. Intriguingly, the Twists and the HDACs appear to interact on a functional level in the regulation of the expression of their target genes This renders a functional interaction between HDAC4, HDAC9, TWIST1 and TWIST2 during AGA development likely, which may contribute to (i) the androgen-induced follicle miniaturization and (ii) the observed anagen shortening and premature catagen entry.(1)
This genetic variation is likely to influence a critical stage of the complex biological cascade that ultimately results in the phenotype.
In recent years, numerous molecular genetic studies have been performed to identify genes that contribute to AGA. The main aim of these studies was to generate novel insights into the biological basis of the following key pathophysiological features of AGA:
- The strict androgen dependency of the AGA phenotype
- The stringent restriction of AGA to defined subpopulations of scalp hair follicles
- Progressive anagen shortening and premature entry into the catagen stage, and
- The abnormal transformation of terminal into vellus hair follicles.
This region is flanked by two genes, which encode for the androgen receptor (AR) and the ectodysplasin A2 receptor (EDA2R), respectively. (1,5)
In view of the androgen dependency of the AGA phenotype, the AR is presumed to be the most plausible candidate gene for AGA and has previously been studied in this context. The second candidate gene in this region is EDA2R, which has been reported to activate JNK and NF-jB signaling, the latter being implicated in anagen maintenance (6) . While AR expression has mainly been observed in dermal papilla cells and sebaceous gland, EDA2R expression has been demonstrated in the mouse hair bulb and in differentiating hair matrix cells . However, follow-up analyses conducted to date could neither confirm nor exclude the AR or EDA2R as the true causative gene, or lead to the identification of the causal variant(s)(6). Moreover, no plausible explanation has yet been provided for why a genetically determined overall functional effect on AR signaling should result in hair cycle abnormalities and abnormal terminal to-vellus transformation in specific skin regions only, whereas the growth of hair follicles elsewhere remains normal and is in fact stimulated by the same ligand (dihydrotestosterone). Further studies are warranted to elucidate the connection between genetic variation at the AR/EDA2R-locus and the androgen dependent development of the AGA phenotype.(7,8) The remaining 11 associated regions are located on the autosomes. This is of particular interest, as in males, the X-chromosome is inherited from the maternal side. Thus, the association at the X-chromosomal AR/EDA2R-locus – as for any association at an X-chromosomal locus – does not explain the resemblance in AGA patterns observed between affected fathers and their sons.(9,10) Thus, this resemblance is either conferred through genetic variation of the Y-chromosome, which is inherited from the paternal side, but contains very few genes, or through genetic variation of the autosomes, which are inherited in equal measure from the father and the mother. The latter contain the vast majority of all human genes, including some already implicated in AGA.(1,4,5)
the genes identified to date explain only a limited proportion of the genetic variance, and thus, the prediction accuracy remains limited (11,12)
Epidemiological studies have shown that AGA patients are at increased risk for benign prostate hyperplasia, prostate cancer, cardiovascular disease (e.g. hypertension, coronary heart disease and myocardial infarction) and metabolic syndrome. However, no shared genetic factors for AGA and these associated diseases have yet been identified, and the overlapping biological mechanisms and common pathophysiological mechanisms remain unknown.
- Heilmann-Heimbach, S., Hochfeld, L. M., Paus, R. and Nöthen, M. M. (2016), Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us?. Exp Dermatol, 25: 251–257. doi:10.1111/exd.12965
- Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci. 1951;53:708–28.PubMedCrossRef
- Ellis, J.A., Stebbing, M., Harrap, S.B., 1998. Genetic analysis of male pattern baldness and the 5alpha-reductase genes. J. Invest. Dermatol. 110, 849–853.
- Ellis, J.A., Stebbing, M., Harrap, S.B., 2001. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J. Invest. Dermatol. 116, 452–455
- Birch MP, Messenger AG. Genetic factors predispose to balding and non-balding in men. Eur J Dermatol. 2001;11:309–14.PubMed
- Gan DC, Sinclair RD. Prevalence of male and female pattern hair loss in Maryborough. J Investig Dermatol Symp Proc. 2005;10:184–9.PubMedCrossRef
- Lee WS, Lee HJ. Characteristics of androgenetic alopecia in Asian. Ann Dermatol. 2012;24(3):243–52.PubMedCrossRefPubMedCentral
- Bas Y, Seckin HY, Kalkan G, Takci Z, Citil R, Önder Y, et al. Prevalence and types of androgenetic alopecia in north Anatolian population: a community-based study. J Pak Med Assoc. 2015;65(8):806–9.PubMed
- Küster W, Happle R. The inheritance of common baldness: two B or not two B? J Am Acad Dermatol. 1984;11(5 Pt 1):921–6.PubMedCrossRef
- Yip L, Rufaut N, Sinclair RD. Role of genetics and sex steroid hormones in male androgenetic alopecia and female pattern hair loss: an update of what we now know. Australas J Dermatol. 2011;52:81–8.PubMedCrossRef
- Hayakawa K, Shimizu T, Ohba Y, et al: Intrapair differences of physical aging and longevity in identical twins. Acta Genet Med Gemellol 1992;41:177–185
- Liu F, Hamer M A, Heilmann S et al. Eur J Hum Genet 2015: doi:10.1038/ejhg.2015.220.[Epub ahead of print].