New Genetic Link to Male Pattern Hair Loss Identified

A glance in the mirror as you head out. A reflection in a car’s paintwork before you meet a date. Men, ever catch yourself checking your hairline?

Up to 80% of men with European ancestry will lose their hair as they age. We know that male pattern baldness is mostly inherited via our mother on the X chromosome.¹ Predicting when we might lose our hair, however, is more complicated than taking a look at our maternal grandad’s crowing glory. A 2023 research paper published in Nature Communications indicates an answer might be on the way. German geneticists compared the DNA of over 70,000 British men in search of genes that tell us how your fuzz will fare.²

Hair Loss and Heredity

In the race to figure out how genetics shape our hairline, researchers have been focusing their efforts on large genome-wide association studies. Several teams have investigated how common genetic variants relate to patterns of men’s hair loss.^{3 4 5}“Common variants” are mutations or versions of a DNA sequence common to many people.

Small variations in DNA code were inherited in the same patterns as androgenic hair loss. This allowed the researchers to make a hair loss “risk profile”. A geneticist could use the profile to predict the odds of when and where a man might start to lose his hair. What’s more, male pattern balding can be an early warning for the onset of age-related conditions such as cardiovascular or metabolic problems. This research might seem harebrained to those blessed with long-living locks, but androgenic hair loss is an indicator for invisible health conditions.

Correlation Is Not Necessarily Causation

If a geneticist can make an estimate of when you should invest in clippers, does it mean a cure is on the way? Well, the markers share a pattern of inheritance with male androgenic baldness, but they aren’t always involved in causing it.

We often find “common” genetic variants on non-coding, spacer parts of chromosomes. This is useful for making guesses about whether you’ll lose your hair, but it doesn’t tell us why your follicles fail. You could think of it as similar to how trucks with rust often break down. The rust might warn you against buying the truck, but it can’t tell you anything much about how well the engine works. University of Bonn geneticists led by Dr. Stefanie Heilmann-Heimbach took advantage of the UK biobank to take a look under the hood.

Earlier work had already shown that the number of genes involved in hair loss is huge. There are so many steps to making a hair, that a mutation anywhere along the way could cause a problem down the road. This means that many different gene mutations could have the same outcome. For example, different types of defect could occur in a fuel line, but they all prevent gasoline from making it into the combustion chamber.

Revelatory Rarities

If you think about it, individual variations, will each occur in small numbers of people. Grouped together, however, or in different combinations, these individual changes lead to a common point of failure.

Gene pathways that decide our height, skin tone, how our hair grows, etc., work in a similar way. Each individual mutation is rare but they are all involved in related processes. Because so many genes could be involved in this complicated mess, you need an enormous number of volunteers to find mutations that group together. You would also need an extraordinarily powerful computer to run the complicated algorithms needed to comb through billions of DNA base pairs.

Super-speedy computer processing power and a huge anonymized DNA database courtesy of the UK’s biobank, give researchers unprecedented opportunities to dig into these problems.

Hacking Hair Loss

The scientists gathered over 70,000 Caucasian male DNA profiles from the UK database. Luckily for the researchers, the anonymous DNA donors aged between 39 years old and 89 also provided information about their health and physical appearance. This included details of if and when they had started to lose their hair and which parts were thinning. They split the men into groups depending on how old they were when they started to lose their hair. The researchers also noted whether their crown or hairline was more affected. They then used powerful DNA sequence scanning and matching tools to identify rare genetic variations that cropped up more often in each subset. Next, they flagged variants that associated with early or late hair loss, and whether the hair thinning started on the crown or at the hair line.

The researchers grouped those variants based on their physical location on each chromosome. Then, they zoomed in and look at stretches of DNA where more of the rare variants seemed to cluster. Finally, they narrowed the sequences down to genes. The researchers calculated which genes most often had some kind of mutation if the owner had male pattern baldness. A gene is a DNA sequence that encodes information. It could be the blueprint for a protein, or a sequence that influences how and when a protein is made.
The sequence surveyors discovered that when they analyzed the 72,469 British DNA profiles with several different analytical tools, five genes showed up with a “hit” for hair loss every time. Two of the genes (EDA2R and WNT10A) were already flagged in previous studies but the Bonn researchers could provide a stronger statistical basis for the link. The other three genes (HEPH, CEPT1, and EIF3F) were a surprise.

New Genes for Male Pattern Baldness?

When the researchers investigated the five genes, all of them were involved in hair growth and corresponded to proteins found in follicles. Some of these genes cause other forms of skin and hair condition. For example, WNT10A is associated with disorders of hair and teeth formation. Mutations in the WNT10A gene can cause a rare condition that stops hair growing past a certain short length.⁶

Another curious outcome was that in addition to being involved in hair follicles, researchers have linked the EIF3F gene with alcohol use.⁷ Bizarrely, researchers have found correlations between alcohol use and hair loss.⁸ This is a remakable result. Does this mean hair loss and alcoholism are linked? Does one lead to the other? Is the same gene that makes your hair stop growing also involved in the neuroscience of compulsive behaviour? This is a great illustration of just how complex the relationships between inheritance of genes and their final effects can be.

Trich or Treat

While this study is noteworthy for having identified new five candidate genes underlying male pattern baldness scientists still have a lot of work to do. Trichologists need to probe these genes to see what exactly they are for, and how the different variants behave in comparison to each other. There is also potential for the algorithm and analysis tools to be refined and improved over time to become more sensitive. The biobank has many more secrets to give up. Perhaps we might not be too far off a DNA test for baldness after all.

Since the dawn of civilization, hairdressers and physicians have been looking for ways to understand and combat hair loss in its various forms. From wigs to magic potions, we’ll try it all if it means a good head of hair. If subsequent work reveals that any of these five genes are responsible for male pattern baldness, we could be about to see a revolution in hair loss science. Economists estimate that the market for hair loss remedies is up to $3 billion annually. With that much money to spend, you can bet your toupée that there will be intense interest in developing drugs.

References

1. Heath AC, Nyholt DR, Gillespie NA, Martin NG. Genetic Basis of Male Pattern Baldness. J Invest Dermatol. 2003;121(6):1561-1564. doi:10.1111/j.1523-1747.2003.12615.x ↩︎
2. 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 ↩︎
3. Chen Y, Hysi P, Maj C, et al. Genetic prediction of male pattern baldness based on large independent datasets. Eur J Hum Genet. 2023;31(3):321-328. doi:10.1038/s41431-022-01201-y ↩︎
4. Yap CX, Sidorenko J, Wu Y, et al. Dissection of genetic variation and evidence for pleiotropy in male pattern baldness. Nat Commun. 2018;9(1):5407. doi:10.1038/s41467-018-07862-y ↩︎
5. Heilmann-Heimbach S, Herold C, Hochfeld LM, et al. Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness. Nat Commun. 2017;8(1):14694. doi:10.1038/ncomms14694
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6. Short anagen hair syndrome is caused by mutations in the WNT10A gene and has a genetic overlap with male pattern hair loss. British Journal of Dermatology. 2023;189(6):e112. doi:10.1093/bjd/ljad416 ↩︎
7. Wang Q, Dhindsa RS, Carss K, et al. Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature. 2021;597(7877):527-532. doi:10.1038/s41586-021-03855-y ↩︎
8. Severi G, Sinclair R, Hopper JL, et al. Androgenetic alopecia in men aged 40–69 years: prevalence and risk factors. British Journal of Dermatology. 2003;149(6):1207-1213. doi:10.1111/j.1365-2133.2003.05565.x
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