Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa

[Simon M]

Thanks, @Woolie, and I also thought it was interesting about the value of GWAS

I think we might be slightly misunderstanding each other so let me start by summarising what I understand from what you said:

1. Anorexia nervosa is primarily an OCD-type of behaviour.

2. The link with metabolic-associated SNPs is primarily that people with these are good at becoming and remain thin and so likely to get a make sense of agency from such behaviours.

The OCD things make sense (though there's also an association with major depressive disorder and depressive symptoms, which are both associated with low motivation).

The idea that people with low BMI are good at becoming and remain thin and gain agency from this is more debatable. My experience of being thin along with @Mirthriel 's family and other people I know is that there is no effort involved. We are just thin and pretty much eat what we like. I know that's annoying to others! I suspect that low BMI people are those who make a real effort and those who make none. And so the of the importance of effort and agency/satisfaction in anorexia is uncertain (or maybe there is research on this already).

The idea of the metabolic genetic differences making it easier to achieve and sustain anorexia certainly makes sense.
However, it would be good to know if everyone who developed anorexia was previously been thin.

It's worth repeating that the metabolic SNPs held up even after correcting for SNPs associated with low BMI:

Because low BMI is pathognomonic of anorexia nervosa, we investigated the extent to which genetic variants associated with BMI accounted for genetic correlations with metabolic and anthropometric traits. First, covarying for the genetic associations of BMI (Methods) led to a mild but statistically non-significant attenuation of the SNP-rg between anorexia nervosa and fasting insulin, leptin, insulin resistance, type 2 diabetes and HDL cholesterol (Supplementary Tables 14, 15), suggesting that anorexia nervosa shares genetic variation with these metabolic phenotypes that may be independent of BMI.

Data on the long-term BMI of such people before they developed anorexia would help shed light onn this.

I don't doubt the central role of psychological factors in anorexia nervosa (which is also supported by the GWAS). The debate is about the role of metabolic and related factors.

One view is that they basically provide more fertile ground for psychological factors to flourish. Another possibility is that they could play a more fundamental role, at least in making recovery more difficult.

A striking feature of the illness believed to be purely psychological is the poor results of psychological treatments aiming to help people to put on weight

Perhaps metabolic factors make it very difficult for some people to do so. (I am always struck by how hard it the me to put on weight, even when I eat like a horse.) Perhaps, once in an anorexic state, the metabolism of some works against weight gain.

Given the poor outcomes it surely makes sense to explore such a promising lead. It could lead to, for instance, drug treatments or dietary regimes that would help weight gain, in conjunction with psychological approaches. I guess that I am reluctant to simply assume that metabolic factors, highlighted by the GWAS, only have a secondary part to play in the absence of clear evidence that this is the case.

 

[Woolie]

Interesting discussion, @Simon.

I need to do proper justice to all your points, but wanted to start with one or two:

The idea that people with low BMI are good at becoming and remain thin and gain agency from this is more debatable. My experience of being thin along with @Mirthriel 's family and other people I know is that there is no effort involved. We are just thin and pretty much eat what we like. I know that's annoying to others! I suspect that low BMI people are those who make a real effort and those who make none. And so the of the importance of effort and agency/satisfaction in anorexia is uncertain (or maybe there is research on this already).

The other possibility is that the link with low BMI etc. is completely spurious and that its caused by a high rate of misdiagnosis of low BMI people as having anorexia when they don't.

A striking feature of the illness believed to be purely psychological is the poor results of psychological treatments aiming to help people to put on weight

It doesn't respond well to treatment, most people who have issues with weight loss continue to have them for a long period of their lives. Its more like, maybe substance abuse, than it is a simple phobia. In the sense of being a lifelong struggle. But many people do gradually recover with time and if they find other good things in their lives.

If you talk with some people who've had anorexia, you get more of an idea of the struggle of it all.

It has also occurred to me that what distinguishes people with anorexia nervosa from those with other eating disorders (e.g., bulimia) is the success they have in losing weight. That could also be playing a part here.

Another possibility is that some of those metabolic correlates are in some way associated with the OCD trait. It probably does more than just make you prone to OCD.

Given the poor outcomes it surely makes sense to explore such a promising lead. It could lead to, for instance, drug treatments or dietary regimes that would help weight gain, in conjunction with psychological approaches. I guess that I am reluctant to simply assume that metabolic factors, highlighted by the GWAS, only have a secondary part to play in the absence of clear evidence that this is the case.

This is a problem with anorexia. People with the disease will not take any drug that they think will make them put on weight. This eliminates most anti-anxiety medications and also antidepressants. They certainly won't be open to treatments that directly involve putting on weight. That's the whole problem.

However, it would be good to know if everyone who developed anorexia was previously been thin.

This varies a lot. Some have, some haven't. I've heard many stories of people who began to lose weight because there were genuinely plump, but then kept going, couldn't hit the "off switch", as it were.

The OCD things make sense (though there's also an association with major depressive disorder and depressive symptoms, which are both associated with low motivation).

I didn't pay that much attention to the other psychiatric correlations because those conditions are so heavily overlapping, and they might not be picking out any genuinely unique causal factors. The high intercorrelations between them also roused my suspicions.

 

[Woolie]

One more:

Perhaps metabolic factors make it very difficult for some people to do so. (I am always struck by how hard it the me to put on weight, even when I eat like a horse.) Perhaps, once in an anorexic state, the metabolism of some works against weight gain.

Constant vigilance and absolute focus on the task of keeping weight off, that's how they do it. Most know the calories of every piece of food they eat and the number of hours of exercise that will be required to compensate for it (intense exercise is a very common feature of anorexia). If forced to eat, they will often resort to strategies to minimise the calories they take in - like laxatives, or self-induced vomiting. That's what I meant by its not at all like just being naturally thin.

 

[Russell Fleming]

This is probably off-topic, but as I happen to be here for a nice change, I thought I would ask:

Would it be worthwhile doing a similar study to investigate if/why people who were previously at the correct BMI prior to having M.E. seem (and I dare say personal experiences are variable) to (often dramatically) lose weight in the early years of illness, and then become overweight in the latter years as the illness appears to enter a chronic stage?

Or might it be argued that it's 'simply' a consequence in the latter years of an inability to be active and of taking in too many calories?

N.B. The above is my experience over 20 years of M.E. But I am not the best by any means at controlling calorie intake. I tend now to regard food - when my appetite is aroused which isn't always the case by any means - as a suitable reward for living with this damned disease.

Thanks

Russell

 

[Diluted-biscuit]

1. Anorexia nervosa is primarily an OCD-type of behaviour.

As you mention that I’d just like to add this.

As someone with OCD is important for people that haven’t experienced this to remember that it will make you do absolutely insane things to the point of utter self destruction. Imagine the compulsion you’d feel to run into a burning building if one of your children were trapped inside. That is the level of compulsion we are talking about for a lot of people with OCD and related conditions. It’s just that they are about things that aren’t actually dangerous or don’t need to be done instead.

It’s very easy for me to imagine someone starving themselves to death with anorexia nervosa however hungry they feel.

This research is still very interesting because maybe for some people treating the issues caused by these genetic factors could help make CBT and other therapies more effective.

 

[lansbergen]

Would it be worthwhile doing a similar study to investigate if/why people who were previously at the correct BMI prior to having M.E. seem (and I dare say personal experiences are variable) to (often dramatically) lose weight in the early years of illness, and then become overweight in the latter years as the illness appears to enter a chronic stage?

I lost weight till the stage I was skin over bone and stayed that way till I started taking the immunemodulator. Then I became thick and after several years I started to lose weight. Now I have a normal figure.

 

[Simon M]

Thanks,@Woolie, lots of good points there and I now know quite a lot more about anorexia nervosa.

There are indeed several possible ways in which the association with metabolic and related factors SNPs can be explained non-accordingly. But also no clear evidence that they can't play the causal role suggested by the GWAS results. We just don’t know. So given the severity of the disease and the lack of good treatment options I would still be in favour of research to establish whether or not metabolic factors do play a significant causal role. Even if, as you point out, it is not clear at this stage how those findings might be applied to treatment.


This will be my last post on the thread because I am getting migraines every day at the moment. Thanks for a really good discussion.