Genetic Future

Baldness genes: one old, one new

hillmer_baldness_chrplot.jpgFrom a geneticist’s point of view, male pattern baldness – also known as androgenic alopecia – is a tempting target. Baldness is common in the general population, with a prevalence that increases sharply with age (as a rule of thumb, a male’s percentage risk of baldness is approximately equal to his age, e.g. 50% at age 50, and 90% at age 90), so there are no shortage of cases to study. It’s also a strongly heritable trait, with about 80% of the variation in risk being due to genetic factors. Finally, baldness has been reported to be associated with a wide range of diseases such as prostate cancer, heart disease and diabetes, so learning about the genes that underlie this condition may help to dissect out the molecular pathways behind more serious disorders.

So it was only a matter of time before researchers targeted baldness with their favoured tool of the moment, the genome-wide association study. This week two separate groups published the results of genome-wide scans for baldness genes in the prestigious journal Nature Genetics. In both cases, their findings strongly support a known genetic association with the androgen receptor gene on the X chromosome, and also highlight a new region on chromosome 20 with a smaller (but still significant) effect on baldness risk.

I’m a little late to the party on this story – see posts by Razib, Hsien, Grace and Erin from 23andMe – but there are some interesting facets to this story that warrant a little extra attention.

The candidate gene approach got there first
One of the most striking findings of these studies is the massive signal of association around the androgen receptor (AR) gene, which is located on the X chromosome – it’s a clear outlier on the signal plot shown below (each dot is a single genetic variant, with each chromosome labelled in alternating colours, and the height on the Y axis is the strength of the association with baldness). In contrast, the novel association on chromosome 20 is fairly modest.

i-82eac652dafa6b5ff71d94ab5388e32d-hillmer_baldness_chrplot.jpg

The unusual thing about this signal is that the association between the AR gene and male pattern baldness has been known since 2001, when it was reported by Justine Ellis from the University of Melbourne (as an aside, The Spittoon erroneously suggests that the first report was in 2005). This is unusual because the pre-genomic era of “candidate gene” association studies, in which only a few selected genes at a time were screened for associations with a disease or trait, was notoriously bad at finding the most important genes. In most cases, the top hits in recent genome-wide association studies are in genes that would never have been identified by the candidate gene approach (e.g. FTO and obesity, the 5p13.1 gene desert in Crohn’s disease). Baldness thus represents a rare success story for the candidate gene approach.

The androgen receptor was originally selected for analysis by Ellis on the basis of biological plausibility – it’s well-known that baldness is associated with the testosterone pathway, and the androgen receptor is the molecule that signals testosterone’s presence to cells all over the body. This means the chromosome X result from these genome-wide studies comes with an immediate biological explanation; unfortunately, the same cannot be said for the chromosome 20 signal.

It’s unclear which gene is the culprit on chromosome 20
Both papers highlight the same stretch of DNA on chromosome 20 as the second strongest signal of association (although the two studies highlight different markers as the top hit, both top markers fall within a region of high linkage disequilibrium – which is just a fancy way of saying that they’re almost always inherited together, so they’re almost certainly both tagging the same underlying causal variant). However, unlike the chromosome X story, there’s no obvious candidate gene lurking in this region – the nearest gene (PAX1) is almost 200,000 base pairs away, and has no known role in the testosterone pathway.

One of the studies provides experimental data showing that PAX1 is expressed in the scalp – but it’s also expressed (and at much higher levels) in muscle and thymus, so this isn’t compelling evidence of a causal role in hair loss. It will take some serious experimental work to unravel the real genetic culprit in this region.

HairDX may be testing the right gene, but the wrong marker
The genetic testing company HairDX offers testing of androgen receptor variants to predict the risk of premature baldness in both males and females. For their male test they examine the marker rs6152, which is located close to the beginning of the androgen receptor gene, but more than 250,000 bases away from the best hit in either of the two genome-wide studies. This suggests that the predictions made by the HairDX test could well be substantially improved by shifting to different markers (and, of course, incorporating markers from the chromosome 20 region).

I’ll be discussing the current HairDX tests in more detail over the next few weeks. For the moment, let’s just say that they’re not something I’ll be rushing out to purchase any time soon.

Genes –> baldness cure?
There are very few things on the internet more depressing than a Google search for “baldness cure” – in a single click you are transported into a sordid world of shame, desperation and rampant greed; ad-riddled forums for lonely men looking for a way to restore their once-luxurious manes, and an army of clinicians and researchers willing to sacrifice their credibility for a share of the resulting cash. As in any medical arena fuelled by desperation, that cash is plentiful (one of the Nature Genetics studies notes that annual sales of a single anti-baldness treatment recently surpassed $405 million).

To pharmaceutical companies baldness must be almost as good a target as obesity: it’s extremely common, afflicts the wealthy as well as the poor, and its sufferers will readily fork over cash for a potential cure. But to find effective treatments, big pharma needs to have a clear idea of how baldness occurs at the molecular level – and that, in theory, is where genetic studies can help. By finding new genetic variations that influence baldness risk, genome scans might highlight unexpected pathways that ultimately lead to new drug targets.

However, these two new studies haven’t provided much to help feed the wallets of pharmaceutical executives: the androgen pathway has long been known to influence baldness risk, and is already targeted by a number of existing baldness drugs (e.g. finasteride, a.k.a. Propecia), while the chromosome 20 region doesn’t yield any clear-cut targets or clues regarding baldness pathways.

Judging from the chromosome scan shown above there are no more low-hanging genes on the baldness tree; it’s going to be extremely difficult (i.e. requiring much larger sample sizes and/or different research approaches, such as large-scale sequencing) to drill down to find the next tier of small-effect risk genes. However, that’s precisely what will be required for effective molecular dissection of the genetic basis of baldness.

Perhaps if a fraction of the money from online sales of dubious baldness therapies went into actual hair loss research we’d have answers more quickly – but I won’t be holding my breath.

References
J Brent Richards, Xin Yuan, Frank Geller, Dawn Waterworth, Veronique Bataille, Daniel Glass, Kijoung Song, Gerard Waeber, Peter Vollenweider, Katja K H Aben, Lambertus A Kiemeney, Bragi Walters, Nicole Soranzo, Unnur Thorsteinsdottir, Augustine Kong, Thorunn Rafnar, Panos Deloukas, Patrick Sulem, Hreinn Stefansson, Kari Stefansson, Tim D Spector, Vincent Mooser (2008). Male-pattern baldness susceptibility locus at 20p11 Nature Genetics DOI: 10.1038/ng.255

Axel M Hillmer, Felix F Brockschmidt, Sandra Hanneken, Sibylle Eigelshoven, Michael Steffens, Antonia Flaquer, Stefan Herms, Tim Becker, Anne-Katrin Kortüm, Dale R Nyholt, Zhen Zhen Zhao, Grant W Montgomery, Nicholas G Martin, Thomas W Mühleisen, Margrieta A Alblas, Susanne Moebus, Karl-Heinz Jöckel, Martina Bröcker-Preuss, Raimund Erbel, Roman Reinartz, Regina C Betz, Sven Cichon, Peter Propping, Max P Baur, Thomas F Wienker, Roland Kruse, Markus M Nöthen (2008). Susceptibility variants for male-pattern baldness on chromosome 20p11 Nature Genetics DOI: 10.1038/ng.228