Hair Loss Genetics - Bernstein Medical - Center for Hair Restoration
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Huffington Post on Hair Loss Genetics

Dr. Bernstein contributed to an article on hair loss genetics published in Huffington Post. In the article, “Sorry, You Can’t Just Blame Your Mother’s Father for Your Thinning Hair” Dr. Bernstein addresses the common myth that hair loss is inherited exclusively from the mother’s side of the family – and, more specifically, from your mother’s father. While your mother’s (or maternal grandfather’s) genes can be the culprit, the characteristics of your hair are influenced by many different genes that may come from either or both sides of your family.

The confusion stems from the fact that men inherit their X chromosome from their mother and a key gene involved in hair loss is found on the X chromosome.

Dr. Bernstein explains:

The androgen receptor gene is an X-linked gene, so there’s a slightly greater incidence of it following the mother’s side of the family than the father’s side, but genetic hair loss is polygenetic and the expressivity is very variable, so both sides can contribute to someone’s hair loss.

Dr. Christopher Cunniff, a clinical geneticist at Weill Cornell Medicine and New York-Presbyterian Hospital, added a comment that the genes most clearly identified as having influence on hair texture or color have not been found to be located on the X chromosome.

The article discusses hair loss genetics and a range of factors affecting the characteristics of one’s hair.

Image c/o: Ruigsantos via Getty Images

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What are the chances that I will go bald? How bald will I be? Can I know for sure? These are among the most common questions we get from patients in our hair loss consultations. Despite extensive knowledge about the mechanisms and causes of androgenetic alopecia (common baldness), the answers to these questions have been a bit hazy. New research has sharpened the focus on the genetic mix that results in hair loss and has enabled more accurate predictions. A study published in February 2017 in the journal PLoS Genetics identified over 250 gene locations newly linked to hair loss. Using this information, researchers more accurately predicted severe balding compared to previous methods.

Background

We know that susceptibility to hair loss is driven by genetics. One in two men in their 50s experience some degree of balding, with that proportion increasing to over 60% of men aged 60 and over. We also know that one of the most important genes in hair loss, called the androgen receptor (AR) gene, is located on the X chromosome. Outside of that, knowledge of the precise genetic makeup resulting in baldness is sparse and there is wide variation in balding patterns. Some genetic tests, such as the HairDx test, have been developed to predict a patient’s risk of balding, but lack the ability to determine its severity. To date, the best method for predicting the extent of future hair loss is to have an experienced physician take a personal and family history and perform a physical examination that includes an assessment of miniaturization of scalp hair.

Developing a more thorough understanding of the complex genetic relationships that result in hair loss will be important in clinical practice as these relationships may help predict future hair loss and guide methods of treatment.

The Study

Researchers selected a pool of more than 52,000 men with male pattern baldness from UK Biobank. This is a massive database of over half a million people aged 40-69 years with information accumulated from 2006 to 2010. This pool was over four times the size of the previously largest hair loss study. Researchers applied a genome-wide association study (GWAS) to a cohort of about 40,000 men and identified 287 statistically important gene locations (loci) linked to varying degrees of baldness — more than 35 times the eight genetic signals found in the previous largest study.

Using this set of 247 loci on non-sex, or autosomal, chromosomes and 40 loci on the X chromosome, the researchers analyzed the remaining 12,000 men for predictive patterns. The results indicated that the predictive value of using this set of gene loci was 0.78 for severe hair loss, 0.68 for moderate hair loss, and 0.61 for slight hair loss. When the subject’s age was added, the predictive score improved to 0.79 for severe hair loss, 0.70 for moderate hair loss, and 0.61 for slight hair loss. Subjects whose individual scores, based on their genetic makeup, were below the mid-point of the range of scores were significantly more likely to have no hair loss than severe hair loss. By contrast, almost 60% of subjects whose individual scores were in the top 10% of the range of scores were moderate to severely bald.

While the predictions were not extraordinarily accurate – the authors characterized the accuracy as “still relatively crude” – they did show a distinct improvement in predictive accuracy over prior studies.

Summary

Hair loss is a serious concern for many people. Research shows that men with extensive hair loss may experience significant psychosocial impacts such as reduced self-image and reduced social interactions. Some studies have associated baldness with increased risk of prostate cancer and heart disease.

Understanding the complex factors that comprise the genetics of hair loss can help physicians potentially customize treatments based on a patient’s genetic profile and their risk of balding. Beyond that, diagnosing the potential severity of hair loss may help doctors get a head start on treating what could be related life-threatening conditions.

With large databases like UK Biobank, researchers can now drill down into this information and develop increasingly clear, highly granular data sets that can identify complex systems and potentially lead to improved treatments.

References

Hagenaars SP, Hill WD, Harris SE, Ritchie SJ, Davies G, Liewald DC, et al. (2017) Genetic prediction of male pattern baldness. PLoS Genet 13(2): e1006594. doi:10.1371/journal.pgen.1006594

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For four decades, scientists have known about the possibility of using cells derived from the base of hair follicles (dermal papilla cells) to stimulate the growth of new hair. More recently, researchers have been able to harvest dermal papillae, multiply them, and induce the creation of new hair follicles – but only in rats. Now, for the first time, scientists at Columbia University have shown in a new study that they can induce new human hair growth from cloned human papillae. This procedure, called “hair follicle neogenesis,” has the potential to solve one of the primary limitations in today’s surgical hair restoration techniques; namely, the patient’s finite donor hair supply that is available for transplantation.

A significant number of hair loss patients do not have enough donor hair to be candidates for a hair transplant procedure with the percentage of women lacking stable donor hair greater than in men. This technique would enable both men and women with limited donor reserves to benefit from hair transplant procedures and enable current candidates to achieve even better results.

According to co-study leader Angela M. Christiano, Ph.D., of Columbia University in New York, the ground-breaking publication is a “substantial step forward” in hair follicle neogenesis. While the technology still needs further development to be clinically useful, the implications of successfully inducing new hair follicles to grow from cloned hair cells could be a game-changer in the arena of hair restoration. Instead of moving hair follicles from the donor area to the recipient area, as in a hair transplant, follicular neogenesis involves the creation of new follicles, literally adding more follicles to the scalp rather than merely transplanting them from one part of the scalp to another. Regarding the new technique’s possible use as a hair restoration treatment, Dr. Christiano said:

“This method offers the possibility of inducing large numbers of hair follicles or rejuvenating existing hair follicles, starting with cells grown from just a few hundred donor hairs. It could make hair transplantation available to individuals with a limited number of follicles, including those with female-pattern hair loss, scarring alopecia, and hair loss due to burns.”

In hair follicle neogenesis, the physician would harvest a sample of healthy, hair-producing scalp tissue from a patient. The dermal papilla cells in the samples would be isolated and allowed to multiply in a laboratory culture, and then the lab-grown papillae would be injected back into balding areas of the person’s scalp where they would induce skin cells to form into hair follicles that would grow normal adult hairs.

The main hurdle that researchers had to overcome was getting human papillae to aggregate — or clump together — so that it could then develop into a follicle. Cells that are cultured on a flat surface seem to lose their ability to produce hair. Prior studies have shown that rat papillae, unlike human papillae, tend to aggregate spontaneously; a process that makes the next, critical step of forming the hair follicle possible. The research team reasoned that if they could create an extracellular environment in which human cells could aggregate, they could induce the growth of human hair follicles.

The breakthrough came as a result of encouraging human dermal papillae cells to grow in a three-dimensional culture — a spherical mass of cells — rather than in a conventional two-dimensional tissue culture. The 3-D configuration allows the cells to signal one another and direct the formation of a new hair. Normally, a culture is grown in a one-cell layer in a petri dish, however, in order to coax the papillae to aggregate, the researchers used a technique called a “hanging drop culture.” Here, droplets of culture, each containing the requisite number of papilla cells (about 3,000 cells) to form a hair follicle, are placed on the lid of a petri dish. When the lid is flipped upside-down, the force of gravity pulls the papillae into the bottom of the suspended droplet, causing the cells to ‘clump.’ This is similar to what the rat papillae do naturally.

In the study, Christiano and colleagues took dermal papillae from seven donors and cloned the cells in tissue culture. After a few days, the cells were transplanted into human skin that had been grafted onto the backs of mice. In implanting these cultured ‘clumps’ of dermal papillae, the research team induced hair follicle production in five out of seven test samples. Using a technique called gene expression analysis, the researchers were able to determine that the three-dimensional cultures restored 22% of the gene expression found in normal hair follicles, enough to induce the formation of new hairs that genetically matched the human donor’s DNA (rather than the mouse).

While hair cloning and multiplication techniques have been discussed and studied for years, the progress made by Dr. Christiano and her colleagues Colin Jahoda, Ph.D., and Claire Higgins, Ph.D. (the first author on the study), is unprecedented. In identifying the key benefit their procedure might have over current hair restoration practices, Dr. Christiano said:

“Current hair-loss medications tend to slow the loss of hair follicles or potentially stimulate the growth of existing hairs, but they do not create new hair follicles. Neither do conventional hair transplants, which relocate a set number of hairs from the back of the scalp to the front. Our method, in contrast, has the potential to actually grow new follicles using a patient’s own cells.”

In addition to combating male and female pattern genetic hair loss (androgenetic alopecia), the technique has the potential for use as a treatment for patients with severe skin injuries, such as burn victims, or sufferers of chronic conditions like scarring alopecias. In these cases, the absence of hair follicles had limited the usefulness of transplanted skin. With the ability to clone follicles, this problem can potentially be overcome.

Dr. Christiano, a colleague of Dr. Bernstein’s at Columbia University, is a world-renowned hair geneticist and a sufferer of alopecia areata, an autoimmune disease that creates bald spots on the scalp. In investigating the causes of her own balding, Dr. Christiano embarked on a career that led to she and her team identifying multiple genes associated with the disease. Her co-study leader, Dr. Jahoda, is a professor of stem cell sciences at Durham University and co-director of the North East England Stem Cell Institute. The lead author of the study, Dr. Higgins, is an associate research scientist in the dermatology department at Columbia University.

The study called, “Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth,” and published in the Proceedings of the National Academy of Sciences (PNAS). The human hair follicles in this study were donated by volunteer hair transplant patients at Bernstein Medical – Center for Hair Restoration in New York City. We are appreciative of our patients who participated in this research.

Reference
Higgins, C.A., Chen, J.C., Cerise, J.E., Jahoda, C.A., Christiano, A.M.: Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. PNAS, 2013; doi: 10.1073/pnas.1309970110.

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We have previously discussed Dr. Angela Christiano‘s work on hair loss genetics with her team at Columbia University in New York. A review of the 16th annual meeting of the European Hair Research Society; held recently in Barcelona, Spain; brings to our attention new research being conducted by a very astute scientist, Dr. Claire Higgins, who works at Dr. Christiano’s laboratory.

With tissue supplied by Bernstein Medical, Dr. Higgins is studying the inductive properties of the dermal papilla (DP), a group of cells that forms the structure directly below each hair follicle. As outlined in our Hair Cloning Methods page, the dermal papilla is of great interest to hair restoration physicians. Ideally, research of this kind will lead to a breakthrough in hair cloning or hair multiplication which will allow physicians to effectively “cure” hair loss by developing a limitless supply of donor hair that can be used in hair restoration procedures.

A description of Dr. Higgins’ work is provided by the Hair Transplant Forum International:

“After isolating [dermal papilla] from human hair follicles, they grow the human DP cells in spheroid cultures in order to retain their inductive potential. Then they place the dermal papilla spheres between the epidermis and dermis of neonatal foreskin and graft it onto the back of mice. Human [hair follicle] neogenesis can be observed after 6 weeks.”

In essence, the scientists were able to capitalize on the potential of dermal papilla cells to induce the growth of a hair follicle by enclosing the DP cells in a small sphere. When implanted, the DP cells maintained their properties of inducing the development of follicles, and, indeed, follicles did grow.

It is another example of how far our understanding of the biology of hair has come in the last 10 years. And it is another example of scientists closing in on the elusive “hair loss cure.”

Read up on the latest Hair Cloning Research

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Q: There was a retrospective study by Lotufo et al. linking male pattern baldness to heart disease. Do you think there are other links like this for androgenetic alopecia? — J.L., San Francisco, CA

A: Family studies revealed both the androgen receptor locus on the X chromosome, as well as a new locus on chromosome 3q26. Association studies performed in two independent groups revealed a locus on chromosome 20 (not near any known genes) as well as the androgen receptor on the X chromosome.

So far, the genetic studies for androgenetic alopecia (AGA) have not revealed identification of a particular gene other than the androgen receptor, as well as the two candidate regions on chromosomes 3 and 20. Inasmuch as the androgen receptor can be involved in other diseases, this might be a feasible connection. Until candidate genes are identified that underlie AGA, it is impossible to predict where the commonalities might lie.

Excerpted from Angela Christiano, Hair Transplant Forum International 2011; 21(1): 14-15.

Read more about Hair Loss Genetics, and see some other Hair Restoration Answers posts on the topic.

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Rodney Sinclair, MBBS, FACD, MD.
University of Melbourne, Fitzroy, Australia.

SUMMARY of Dr. Sinclair’s Abstract from his presentation at the International Society of Hair Restoration Surgery, 2005 – Sidney, Australia

Twin studies have confirmed the strong heredity of androgenetic alopecia. The purpose of the present study is to explore the genetic basis of androgenetic alopecia by gene analysis. The study compared the sequence of several candidate genes between groups of individuals considered to be most and least genetically predisposed to androgenetic alopecia. Most likely are young males who already have a significant degree of baldness and least likely are those who are older and have no sign of hair loss.

The 5 alpha-reductase genes (SRD5A1 and SRD5A2), aromatase genes, Y chromosome and androgen receptor genes were analyzed. The authors found a significant difference in the frequency of a single base change in the coding region of the AR gene. These results provide good evidence for the involvement of AR in androgenetic alopecia.

Interestingly, 77% of non-bald men carry the version of the AR gene found in bald men. This suggests that the AR gene is necessary but not sufficient for causing baldness. This raises the possibility that other genes are acting in conjunction with AR. For instance, genes other than SRD5A1 and SRD5A2 that control levels of DHT production remain candidates. Given that 5 alpha-reductase is increased in balding scalp, these might include transcription factor genes which regulate the production levels of 5 alpha-reductase. Such transcription factor genes are yet to be identified. The many other genes, known and unknown, that are involved in androgen production, regulation and response may also be involved.

In addition to androgen-related genes, genes involved in patterning, signaling and hair follicle morphogenesis are other potential candidates for future research.

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