A tale of two anorexia genetics studies
Over the past month, there have been two major, news-grabbing studies on the genetics of anorexia. Both of these studies carried headlines saying something like “Anorexia genes found!”
There are several problems with this:
- There are no such thing as “anorexia genes”
- These two studies were VERY different and found VERY different things.
Given that the genetic underpinnings of EDs are a Big Deal in the research and lay communities right now, and that I haven’t covered specific genetics studies thus far, I thought that these studies are actually very good ways to explain how we discover genetic links to illnesses like EDs, and what they do (and don’t) tell us.
The missing heritability
Researchers call it the ‘missing heritability’ issue. It’s not specific to EDs or psychiatric illnesses, although this is where you will hear it discussed most frequently. The issue is that twin studies on anorexia have found that roughly 55% of the reason some twins developed AN and others didn’t was due to genetic factors- factor in confidence ratios, and that percentage can go upwards of 80% (Bulik et al., 2006). The problem was that when researchers went spelunking through the billions of As, Ts, Gs, and Cs in the human genome, they couldn’t consistently identify any gene that was conclusively linked to an increase AN risk. The twin studies were consistent across different populations, indicating that genetics was a major factor in AN (and all EDs), but any actual genes remained mysterious.
Scientists were never expecting to find ‘the’ anorexia gene. They know there would never be one. Genes don’t cause disease–they make mRNA which makes proteins. A gene’s sequence can alter the amino acids that build a protein. The sequence of amino acids in a protein determine the protein’s shape, and the protein’s shape determines how well it works. How well a protein does its job can alter your risk of developing an illness, such as an eating disorder. Given that an eating disorder involves problems not just with food and appetite, but also emotion regulation and reward, there will likely be a whole host of genetic mutations that slightly alter your risk of developing an ED. This can make these genes harder to find because their impact across a population will be small, and researchers won’t be able to find the proverbial ‘smoking gun.’
When researchers begin to look for these types of mutation that contribute risk for developing an illness, they frequently use a technique known as genome-wide association studies (GWAS, pronounced “gee-wass”). In GWAS, researchers search for variations in single nucleotides (known as Single Nucleotide Polymorphisms, or SNPs- pronounced “snips”). They look at the gene sequences in people with an illness and those without and see if any SNPs are more or less common in the individuals with the illness. If they do identify a SNP, then the researchers say that this gene (or area of the genome) is associated with an illness.
It’s what researchers did in a recent paper in Molecular Psychiatry, in which the researchers found an association with variants of the EPHX2 gene and AN (Scott-Van Zeeland et al., 2013). The researchers started with genetic information from 334 individuals, of which 261 had early onset, severe AN and 73 were controls, and began sequencing 152 genes known to be associated with feeding behavior or other aspects of AN (such as GABA, dopamine, and other genes), including the area immediately around the gene. Of all of these 152 genes, the researchers only identified several variants in two different genes.
When they looked closer at a larger group of AN cases and controls, the researchers found that only one gene (EPHX2) was significantly associated with AN in a variety of populations. The gene, whose full name is epoxide hydrolase 2, is an enzyme that regulates cholesterol production. Many sufferers of AN suffer from high cholesterol in the acute stage of illness, which has generally been attributed to the effects of starvation. These new results hint that it might not just be starvation.
It isn’t yet clear how EPHX2 variants that cause an abnormal metabolism of cholesterol would help trigger or maintain anorexia. But Schork noted that people with anorexia often have remarkably high cholesterol levels in their blood, despite being severely malnourished. Moreover, there have been suggestions from other studies that weight loss, for example in people with depression, can lead to increases in cholesterol levels. At the same time, there is evidence that cholesterol, a basic building block of cells, particularly in the brain, has a positive association with mood. Conceivably, some anorexics for genetic reasons may feel an improved mood, via higher cholesterol, by not eating.
“The hypothesis would be that in some anorexics the normal metabolism of cholesterol is disrupted, which could influence their mood as well as their ability to survive despite severe caloric restriction,” said Schork.
The problem with GWAS studies like this is that they are prone to false positives. Sort through enough genetic data and you’re bound to find a link between some SNP and your illness, just like if you start flipping coins you’ll get a streak of tails. You might think you have a trick coin, but it’s really just the vagaries of chance. The researchers tried to guard against it by searching through a variety of populations and getting a large sample size, which is good that variants in the gene were significantly associated with AN in all of these. However, it’s still just one study and all of the populations were European (of course, gene variants can be population-specific, since many populations didn’t mix together that frequently until very recently). My basic response is: it’s promising and interesting and definitely needs more research, but I have seen many strong results fail to be replicated. If someone else finds these results, then I’ll say we’re on to something.
Rare mutations, strong effects
GWAS tends to search for common-ish variants with small effects. Other types of genetic studies look for rare mutations with much stronger effects. On the diagram below, GWAS is at the bottom right. The next study I’m going to talk about is at the top left.
In a separate study published in the Journal of Clinical Investigation, researchers looked at two families in which multiple members had AN or BN across three generations (Cui et al., 2013). In one family, 10/20 members had full-syndrome AN or BN (they excluded EDNOS just to be on the safe side, in case the abnormal eating behavior wasn’t a true eating disorder and instead only looked like one on the surface, due to growing up in an environment where eating disorders were the norm)–tremendously higher than the prevalence you would expect. The researchers first identified regions of interest on various chromosomes and then fully sequenced the genomes of 1-2 people from each family who had AN to look for specific mutations.
In the first family, they found a single nucleotide mutation in the estrogen-related receptor α (ESRRA) gene. All ten individuals with an ED had this mutation, and nine of ten without an ED did not. The protein coded for by ESRRA is a transcription factor and helps to regulate the activity of other genes. Interestingly, so is the other gene mutation found in the second family, HDAC4 (histone deacetylase 4). Even more interesting is that these two genes bind to each other in the cell. The effects of both of these mutations is to decrease ESSRA activity, which somehow increases the risk of developing anorexia.
Unlike the first study, these mutations were identified by direct genome sequencing, and it’s basically pretty much certain that these mutations are responsible for the astronomical rates of AN and BN. The caveat is this: most people with EDs probably don’t have these mutations. These are rare mutations with VERY strong effects, unlike most gene variants thought to contribute to AN, which are slightly more common and have smaller effects. Thus a person with an ED likely carries several or even many of these variants that help to tip them over into developing an ED under certain circumstances. Each person’s risk of developing AN will be a combination of environmental and genetic effects. Some mutations have a much stronger genetic effect, such that environmental factors play a much smaller role in the developing of an ED. Other people may have environmental factors that dominate their own risk. Most people will be in between.
A genetic link to AN doesn’t mean that your chances of developing anorexia are somehow foretold on a DNA magic 8 ball hidden deep in the nucleus of your cells. It doesn’t mean that there’s nothing you can do about your disorder or that you’re totally screwed by your double helix. It just means that some people are much more likely to develop an ED than others.
Yes, both of these studies found genes linked to AN, but they are very different genes with very different effects. The genetics of EDs is extremely complicated!
Bulik, C. M., Sullivan, P. F., Tozzi, F., Furberg, H., Lichtenstein, P., & Pedersen, N. L. (2006). Prevalence, heritability, and prospective risk factors for anorexia nervosa. Archives of general psychiatry, 63(3), 305. doi:10.1001/archpsyc.63.3.305
Cui, H., Moore, J., Ashimi, S. S., Mason, B. L., Drawbridge, J. N., Han, S., … & Lutter, M. (2013). Eating disorder predisposition is associated with ESRRA and HDAC4 mutations. The Journal of Clinical Investigation, 123(11), 0-0. doi:10.1172/JCI71400
Scott-Van Zeeland, A. A., Bloss, C. S., Tewhey, R., Bansal, V., Torkamani, A., Libiger, O., … & Schork, N. J. (2013). Evidence for the role of EPHX2 gene variants in anorexia nervosa. Molecular psychiatry. doi: 10.1038/mp.2013.91