Of Genes and Eating Disorders

Oct 09 2013 Published by under Behavioral Neuro

Eating disorders like anorexia nervosa and bulimia nervosa are difficult psychiatric disorders. They are especially tragic because, while they may seem like just messed up eating, they are far, far more. Eating disorders have some of the highest rates of death of any psychiatric disease, as malnutrition puts the body at risk.

When we think of eating disorders, though, we tend to think of them from a cultural angle. It's because our culture is so obsessed with thin, no one can ever be thin enough, and so that must bring out eating disorders. It is true that a culture which glorifies skinny the way ours does tend to bring out more extreme dieting than one that does not. But it is also true that eating disorders are far more than the product of a culture which glorifies the size 0. Reports and descriptions of anorexia, for example, date all the way back to the Greeks, and famous case studies that fully described the disorder date from the 1860's. There is clearly a genetic component, anorexia in particular runs strongly in families. There is also a potential sex effect, eating disorders are far more common in women than in men.

Eating disorders are a combination disease, a combination of genetic risks and environmental triggers, including things like stress. Unfortunately, it's been difficult to identify specific genes that predispose people to eating disorders. Studying large populations of people with the disease and find some common genetic variants, for example, but for such a complex disorder that is not dependent on a single gene, many of those will also be present in healthy populations.

Another approach is instead to look at families which have a strong history of eating disorders, to see what common genes are passed down. While this has its own limitations (for example, you then have to look for the occurrence of those genes in the wider population, and being within a single family or two, there are bound to be environmental factors that aren't present elsewhere), it's a way to uncover genetic variants that my have previously gone undiscovered. And it means you might, as they did here, uncover two genes that, when screwed up in very precise ways, result in the same eating disorder.

Cui et al. "Eating disorder predisposition is associated with ESRRA and HDAC4 mutations" Journal of Clinical Investigation, 2013.

The authors of this study focused on two families with a history of anorexia or anorexia/bulimia. From the first family, they were able to get DNA samples from 10 "affected" members with anorexia, and 10 "unaffected" members without. From the second family, they got DNA from 6 "affected" members and 2 "unaffected" members. They analyzed the genomes, looking for common mutations that the affected family members had, but the unaffected ones didn't.

They found that in the first family, all of the affected members had a mutation in ESRRA, an estrogen receptor that can affect how genes are expressed. Only one of the unaffected members had the mutation. In this case, the mutation was a "missense" mutation, resulting in DNA that "codes" for a different amino acid than usual. When they analyzed the mutation, they were able to show that it was possibly damaging. ESRRA is known to play a role in energy balance (including things like food intake), and its expression is increased by things like exercise and food restriction.
(Figure 1A)

In the second family, they found a different mutation. In this one, the DNA change meant that one amino acid was changed for another in in the enzyme histone deacteylase 4 (HDAC4). All 6 of the affected members had the change, while the two unaffected members did not. HDAC4 is involved in things like locomotor activity, but is ALSO involved in maintaining things like body weight.

And what's more...the two proteins, the ESRRA and the HDAC4, interact with each other. HDAC4 blocks the activity of ESRRA. When the authors looked at each of the mutations and how they might affect the interaction, they were able to show that the ESRRA mutation in the first family caused the activity of ESRRA to decrease. The HDAC4 mutation in the second family caused the HDAC4 activity to INCREASE. Since the increase in HDAC4 activity repressed ESRRA activity, the net result is that BOTH mutations result in decreased ESRRA function.

So it could be that this decreased ESRRA function means a lot when it comes to the development of eating disorders. More work needs to be done though, for example, the first family also has a very high rate of OCD, which might confound some of the effects, and the second family had high rates of bulimia, which is similar, but not the same as anorexia. A much bigger sample could help determine how much these two mutations really have to do with eating disorders, and what it could mean for treatment. It would also be very interesting to look at what this means for estrogen. It is very interesting that eating disorders are much more common in women, and ESRRA is an estrogen receptor. But the finding of two genetic mutations that end up having the same result is a big one, and could mean a lot for figuring out where eating disorders come from, and help us find ways to treat them.

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