Researchers have identified rare gene variants that cause male pattern hair loss, also termed androgenetic alopecia.
Male-pattern hair loss is the most common form of hair loss in men, and is largely attributable to hereditary factors. Current treatment options and risk prediction are suboptimal, thus necessitating research into the genetic underpinnings of the condition.
To date, studies worldwide have focused primarily on common genetic variants, and have implicated more than 350 genetic loci, in particular the androgen receptor gene, which is located on the maternally inherited X chromosome.
In contrast, the contribution to this common condition of rare genetic variants has traditionally been assumed to be low. However, systematic analyses of rare variants have been lacking.
"Such analyses are more challenging as they require large cohorts, and the genetic sequences must be captured base by base, e.g., through genome or exome sequencing of affected individuals," explained first author Sabrina Henne, doctoral student at the Institute of Human Genetics at the University Hospital of Bonn (UKB) and the University of Bonn in Germany.
The statistical challenge lies in the fact that these rare genetic variants may be carried by very few, or even single, individuals.
Among other methods, the Bonn researchers used a type of sequence kernel association test (SKAT), which is a popular method for detecting associations with rare variants, as well as GenRisk.
The research involved the analysis of genetic sequences from 72,469 male UK Biobank participants.
Within this extensive data set, Bonn geneticists examined rare gene variants that occur in less than one per cent of the population.
Using modern bioinformatic and statistical methods, they found associations between male-pattern hair loss and rare genetic variants in the following five genes: EDA2R, WNT10A, HEPH, CEPT1, and EIF3F.
Prior to the analyses, EDA2R and WNT10A were already considered candidate genes, based on previous analyses of common variants.
"Our study provides further evidence that these two genes play a role, and that this occurs through both common and rare variants," explained Dr. Stefanie Heilmann-Heimbach, who is a research group leader at the Institute of Human Genetics.
Similarly, HEPH is located in a genetic region that has already been implicated by common variants, namely the EDA2R/Androgen receptor, which is a region that has consistently shown the strongest association with male-pattern hair loss in past association studies.
"However, HEPH itself has never been considered as a candidate gene. Our study suggests that it may also play a role," Henne said.
"The genes CEPT1 and EIF3F are located in genetic regions that have not yet been associated with male-pattern hair loss. They are thus entirely new candidate genes, and we hypothesise that rare variants within these genes contribute to the genetic predisposition. HEPH, CEPT1, and EIF3F represent highly plausible new candidate genes, given their previously described role in hair development and growth."
Furthermore, the results of the study suggest that genes that are known to cause rare inherited diseases affecting both skin and hair (such as the ectodermal dysplasias) may also play a role in the development of male-pattern hair loss.