The finding has one expert questioning why previous research was quick to dismiss these potential diamonds in the rough.
The identification of five rare genetic variants for androgenetic alopecia represents a key building block and serves as an important clinical reminder, says an Australian expert.
Androgenetic alopecia, or male-pattern hair loss, is one of the most common forms of baldness in men.
Previous research revealed genetic factors, such as polymorphisms in the androgen receptor gene, are significant contributors to the condition.
Over 600 independent genetic risk variants have been identified to contribute to androgenetic alopecia, most of which are highly common in men affected by the condition.
“We know male pattern baldness is a complex polygenic condition, but exactly how many genes [are involved] and how they influence the phenotype of baldness is largely unknown, meaning we’re no closer to finding effective treatments,” Dr Leona Yip, a Brisbane-based alopecia specialist.
Now, new German research goes beyond the existing genetic markers found through previous genome-wide association studies.
The research, published in Nature Communications, used exome-based analyses to identify five new genetic variants that, while rare, make significant contributions to androgenetic alopecia.
“Investigations of the functional relevance of rare variants and their interaction with common variants … will eventually improve our understanding of [androgenetic alopecia] pathobiology and may lead to improved risk prediction and identification of affected pathways and can pave the way for the development of personalised therapies,” the authors concluded.
Researchers used genetic and self-reported baldness data from the UK Biobank study. More than 70,000 men, about 50,000 of whom displayed some sign of hair loss (from frontotemporal balding through to complete baldness of the top of the scalp) were included in two types of gene-based analyses, SKAT-O and GenRisk.
Rare variations in five genes displayed significant associations with androgenetic alopecia, which, according to the authors, “offers important insights into [its] biology and may be aetiologically relevant for individual risk”.
Two of the variants identified in the study had previously been identified as potential genetic contributors to androgenetic alopecia – the ectodysplasin A2 receptor gene EDAR2 and the Wnt Family Member 10A gene WNT10A. Both genes are involved in the development and maintenance of tissues arising from the ectoderm, such as hair, teeth and nails.
“These findings suggest that both common and rare variation in these genes contributes to [the] aetiology [of androgenetic alopecia],” the authors wrote.
The remaining three gene variants and their associated proteins – hephaestin (HEPH), choline/ethanolamine phosphotransferase 1 (CEPT1) and eukaryotic translation initiation factor 3 subunit F (EIF3F) – had not previously been associated with androgenetic alopecia. Despite this, they all have links to hair biology or development:
- HEPH encodes a protein that metabolises iron; iron deficiency inhibits haemoglobin production, a necessary part of hair growth
- CEPT1 encodes a protein that creates phospholipids, which promote hair growth in mice
- EIF3F encodes a protein that regulates Notch signalling, which contributes to hair follicle stem cell fate determination.
“These novel links with rare variants are not that surprising as it is likely some monogenic genotrichoses [genetic hair disorders] and male pattern baldness share similar defects in hair follicle programming and development pathways,” explained Dr Yip, whose doctoral research focused on the genetics of female pattern baldness.
“[However], these results may trigger a reflective ‘why didn’t we think of doing it first?’ as most genetic research for male pattern baldness has predominantly only focussed on common genetic variants and been relatively dismissive of the role of rare genetic variants.”
Dr Yip noted there is still a long way to go before commercial testing kits can reliably predict an individual’s risk of androgenetic alopecia, but that these findings are an important piece of the puzzle in understanding how rare variants contribute to the risk.
“These findings remind us that treatment for male pattern baldness is not one size fits all – [there is] a genetic tendency that is governed by common and rare genetic variants that make some treatments more effective than others,” Dr Yip told The Medical Republic.