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New Findings Show How Rare Mutations Affect Male Pattern Hair Loss

A bald man pulling a face.
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Receding hairline, tonsure and finally baldness: A lot is already known about the common gene variants involved in hereditary hair loss in men. Human geneticists from the University Hospital of Bonn ( UKB ) and the Transdisciplinary Research Area “Life & Health” at the University of Bonn have now found out to what extent rare genetic variants contribute to male pattern hair loss, also known as androgenetic alopecia. To do this, they analyzed 72,469 genetic sequences from men of British descent in the UK Biobank and were able to identify a total of five significant genes. Their study also provides additional evidence for genes that are already known. The study results have now been published in the renowned journal “Nature Communications” .

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Androgenetic alopecia is the most common form of hair loss in men and is largely caused by hereditary factors. To date, studies have primarily focused on common genetic variants. So far, more than 350 involved gene loci have been identified worldwide, with the androgen receptor gene located on the X chromosome inherited from the mother being the most notable. The contribution of rare genetic variants to this common disease has, however, been estimated to be low, but systematic analyzes have so far been missing. “Such analyzes are also more difficult because, unlike when looking at common variants, genetic sequences have to be systematically recorded through extensive sequencing of the genomes of those affected,” says first author Sabrina Henne, a doctoral student at the Institute for Human GeneticsUKB and the University of Bonn. Statistically, the challenge is that with rare gene variants only a few or even just individual people carry these specific variants. “That’s why we use gene-based analyzes that initially summarize variants based on the genes in which they are located,” says corresponding author PD Dr. Stefanie Heilmann-Heimbach, research group leader at the Institute for Human Genetics at the UKB and the University of Bonn. Among other things, a type of sequence kernel association test (SKAT), a popular method for detecting association with rare variants, was used, as well as GenRisk, a method developed at the Institute for Genomic Statistics and Bioinformatics (IGSB) at the UKB and the University of Bonn .

Possible relevance of rare variants in hereditary hair loss in men

The research is based on genetic sequences from a total of 72,469 male test subjects in the UK Biobank. Within this extensive amount of data, the Bonn human geneticists, together with researchers from the IGSB and the Center for Human Genetics at the University Hospital of Marburg, looked at rare gene variants that occur in less than one percent of the population. Using modern bioinformatics and statistical methods, they found associations between hereditary male pattern baldness and rare genetic variants in five genes: EDA2R , WNT10A , HEPH , CEPT1 and EIF3F .

EDA2R and WNT10A were already considered candidate genes based on analyzes of common variants. “Our study increases the evidence that these two genes play a role and that this occurs through both common and rare variants,” says Heilmann-Heimbach. HEPH is also located in a genetic region that has already been implicated by common variants, near EDA2R and the androgen receptor, the region that has been consistently most strongly associated with hair loss across past association studies. “ HEPHHowever, itself was never discussed as a candidate gene - our study provides an indication that it could also play a role," says Henne: " CEPT1 and EIF3F are two genes that are located in genetic regions that are not yet associated with hereditary hair loss became. They are therefore completely new candidate genes, with the hypothesis that rare variants within these genes contribute to the genetic predisposition. Also due to their previously described function in the development and growth of hair, HEPH , CEPT1 and EIF3F“The results also suggest that genes already known to cause rare inherited diseases that affect both skin and hair (such as ectodermal dysplasia) also play a role could play a role in the development of male pattern baldness. The researchers hope that the pieces of the puzzle they have found will help to better understand the causes of hair loss and thus both predict the risk more reliably and improve treatment options.

Reference: Henne SK, Aldisi R, Sivalingam S, et al. Analysis of 72,469 UK Biobank exomes links rare variants to male-pattern hair loss. Nat Commun. 2023;14(1):5492. doi: 10.1038/s41467-023-41186-w

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