Preprint Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration

[ME/CFS Science Blog]

The DecodeME questionnaire asked about 'Clinical depression' as one of the other conditions participants might have. It would be interesting to see if the answer to this question determines the similarity to the depression GWAS. In other words, if we see similar results in ME/CFS patients, if those with clinical depression are excluded.

Here's an example of what they found in the first big depression GWAS. Mostly genes involved in neurons and synapses, some pointing to regulation of immune responses and also calcium channel activity.


Source: Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression | Nature Genetics

 

[forestglip]

Does the database also include diseases that ME/CFS is often compared with, such as Multiple Sclerosis, Lupus, or mitochondrial disorders?

The only result I see of these from a search of the words is multiple sclerosis in UK BioBank and it doesn't look to be significant. (Also all results from all tested traits are in the attached files if you want to explore.)

From UK BioBank:

• Multiple Sclerosis:
  • Diagnoses - main ICD10: G35 Multiple sclerosis (rg=-0.0713, p=0.6354)
  • Non-cancer illness code, self-reported: multiple sclerosis (rg=0.0051, p=0.9582)
• The correlation analysis with lupus had an error and didn't work ("WARNING: One of the h2's was out of bounds. This usually indicates a data-munging error or that h2 or N is low.")

 

[ME/CFS Science Blog]

The highest correlation (rg=0.586, p=5.0e-121) is with depression

I suspect you filtered on the lowest p-values? One issue is that this may be affected by the sample size of the trait rather than the strength of correlation with ME/CFS.

Because we also want to avoid having lots of false positives, I tested an arbitrary threshold of p < 0.00005 and then ranked them according to the highest correlation values (rg) using the UK Biobank data. I think there's a clear link to depression, with multiple categories scoring high (but not as high as IBS and CFS). Anxiety is also up there.

Some weirder findings are:

• Never eats dairy products
• Spondylosis

EDIT: update the results to use a bonferroni correction rather than an arbitrary threshold of p < 0.00005. See posts below.

 

[forestglip]

I suspect you filtered on the lowest p-values?

Yes, just sorted by p-value. (And that enormously significant correlation with depression does come from comparing to a study with an enormous sample size: 371,184 depression cases)

Good idea to look at top correlations. I wonder what that milk one is about. Just under your significance threshold though (and slightly above Bonferroni threshold for all traits in the BioBank).

Edit: Sorry, I see there are two milk related correlations, and one is more significant.

 

[Simon M]

Thanks, I suspect this will be one of the areas where the preprint may need to adjust the wording a bit. There does seem to be a link/similarity to depression based on genetic data.

Interesting analysis.

Worth noting that maybe a third of pwME had depression after they relaxed the recruitment criteria. I think they are planning to do a sensitivity analysis with excluding this group. I also gather that depression has a broad signal that correlates with many things (including some gastro diseases (though not so sure on this - I don't know if anyone has seen data on this?)/

 

[ME/CFS Science Blog]

Good idea to look at top correlations. I wonder what that milk one is about. Just under your significance threshold though (and slightly above Bonferroni threshold for all traits in the BioBank).

Thanks, makes more sense to do a bonferroni correction, the results are largely the same. I assumed that those with an rg value of 9999 are unvalid, so after excluding those I got 3167 remaining tests. So the bonferroni p_value is the p value times 3167.

I will update the results above.

 

[forestglip]

I assumed that those with an rg value of 9999 were unvalid

Yes, just to confirm, the BIGAGWAS website says "9999 represents NA for numerical data".

 

[Utsikt]

How was depression status determined? Ever been diagnosed by a psychologist/psychiatrist? By anyone? Questionnaires (that usually ask about lots of things that will flag anyone that’s unwell in general)?

 

[ME/CFS Science Blog]

Worth noting that maybe a third of pwME had depression after they relaxed the recruitment criteria.

I also think that the UK Biobank has a lot of these depression and anxiety related categories and less for autoimmune or mitochondrial disorders.
There also seems to be a difference between the 0.7-0.75 correlation for CFS and IBS and the 0.5-0.55 for the depression categories.

But in all, it does seem that there is some genetic similarity between ME/CFS and depression.

 

[ChronicallyOverIt]

This is rather naive, but what if depression is a secondary factor . As in you become depressed due to ME? Could this signal be due to being depressed because you have ME? Or are these questionnaires narrowing in on pre-ME depression?

 

[Utsikt]

This is rather naive, but what if depression is a secondary factor . As in you become depressed due to ME? Could this signal be due to being depressed because you have ME? Or are these questionnaires narrowing in on pre-ME depression?

This studie is not about if pwME/CFS have depression, but if the genes that are significant for ME/CFS also have been significant in GWASs for depression.

I have no doubt that a lot of depression in ME/CFS is secondary, and a lot of just being sick gets labelled as depression as well.

 

[Hoopoe]

In my experience, the illness in, combination with lack of support and misunderstanding, can easily lead to a lack of pleasant experiences. This deprivation appears similar to depression. I think it would be more accurate to describe it as getting used to having too few good things in life. One gets used to the fact that seeking a positive experience generally does not lead to a positive experience, so there is little drive to do most of the things that a normal person would do to feel good. The few remaining things that give pleasure may be relied upon excessively. The ability to experience pleasure and the desire to do so is intact, but there are far fewer opportunities to experience pleasure without negative consequences.

In less general terms, if going outside tends to make the person feel unwell soon, or if the later consequence is malaise, the person will have little drive to do so, except in ways that are within the tolerated limits. But one must first develop an understanding of the dynamics at play... that the malaise is a delayed consequence and not random, that one must reduce expectations and do less than one would like. And one must also learn to resist the requests or invitations of other people to do as much as a normal person would in the give circumstance. Other people and systems tend to have a negative impact when they don't take accomodate the illness. There's a lot of learning involved if one starts from a position of total ignorance of the illness and confusion about what is happening and what to do.

The state of PEM can also look similar to depression.

There's probably some overlap between risk genes for depression and ME/CFS, just like there is for various other diseases.

 

[ChronicallyOverIt]

This studie is not about if pwME/CFS have depression, but if the genes that are significant for ME/CFS also have been significant in GWASs for depression.

I have no doubt that a lot of depression in ME/CFS is secondary, and a lot of just being sick gets labelled as depression as well.

Whoops I was thinking epigentics for a second. Yes I see now

 

[forestglip]

This is rather naive, but what if depression is a secondary factor . As in you become depressed due to ME? Could this signal be due to being depressed because you have ME? Or are these questionnaires narrowing in on pre-ME depression?

If you consider that the prevalence of ME/CFS is far lower than depression, then most people in the depression studies wouldn't have ME/CFS. My sense is that it'd be difficult to get such high correlations based on people in the depression studies having ME/CFS if only a small portion of the depression cases have it.

Here's a website with some discussion of what a genetic correlation can mean (number 2 is what you suggested):

1. “Biological” pleiotropy. In this situation, genetic variants that influence one trait also influence another because of some shared underlying biology. For example, genetic variants that influence age at menarche in women have correlated effects on male pattern baldness. Presumably this is because there are some shared hormonal pathways that influence both of these traits, such that altering these pathways has effects on multiple traits.

2. “Mediated” pleiotropy. In this situation, one trait is directly causally influenced by another. This of course means that a genetic variant that influences the first phenotype will have knock-on effects on the second. The classic example here is LDL cholesterol and heart disease: these two traits are positively genetically correlated, and it is now widely accepted that this correlation is due to a causal effect of LDL on risk of developing disease. Identifying this situation is has important medical implications: since LDL is causal for heart disease, then a non-genetic intervention that influences LDL (for example, a drug or an altered diet) should have an effect on someone’s risk of heart disease.

3. Parental effects. For example, imagine that more educated parents pay more attention to the diets of their children, and thus their children have lower rates of obesity. This would be detected in GWAS as a genetic correlation between educational attainment and obesity, though the causal connection between the variant and the two traits is less direct than in the previous two situations.

4. Assortative mating. For example, imagine taller individuals tend to marry individuals with higher socioecomonic status. This would induce a genetic correlation between the traits. What is happening is that the alleles that associated with both traits co-occur in the same individuals (the offspring of these assortatively-mating parents).

Misdiagnosis is another possible reason for genetic correlation not mentioned here. I suppose there's a small possibility of wide-scale misdiagnosis of ME/CFS as depression.

 

[Utsikt]

In my experience, the illness in, combination with lack of support and misunderstanding, can easily lead to a lack of pleasant experiences. This deprivation appears similar to depression. I think it would be more accurate to describe it as getting used to having too few good things in life. One gets used to the fact that seeking a positive experience generally does not lead to a positive experience, so there is little drive to do most of the things that a normal person would do to feel good. The few remaining things that give pleasure may be relied upon excessively.

In less general terms, if going outside tends to make the person feel unwell soon, or if the later consequence is malaise, the person will have little drive to do so, except in ways that are within the tolerated limits. But one must first develop an understanding of the dynamics at play... that the malaise is a delayed consequence and not random, that one must reduce expectations and do less than one would like. And one must also learn to resist the requests or invitations of other people to do as much as a normal person would in the give circumstance. Other people and systems tend to have a negative impact when they don't take accomodate the illness. There's a lot of learning involved if one starts from a position of total ignorance of the illness and confusion about what is happening and what to do.

The state of PEM can also look similar to depression.

Here’s my psychologist’s take:

It looks like depression in terms of doing less, but if you spend a bit of time talking to the patient it’s nothing like it. And if the patient is depressed, it’s usually a completely normal response to a very extreme situation.

Having experienced depression before and during the onset of my illness, I agree.

 

[Hoopoe]

And if the patient is depressed, it’s usually a completely normal response to a very extreme situation.

Yes, the situation can be extremely bad. Being depressed due to genuinely bad circumstances is different from being depressed for no apparent reason (the latter implies that there is an underlying illness that is directly causing the poor mood).

Improving the circumstances is effective in treating the first kind of depression. But this is difficult!

 

[MrMagoo]

Here’s my psychologist’s take:

It looks like depression in terms of doing less, but if you spend a bit of time talking to the patient it’s nothing like it. And if the patient is depressed, it’s usually a completely normal response to a very extreme situation.

Having experienced depression before and during the onset of my illness, I agree.

Same, I had a very good GP who explained that pwME are always trying, they’re always pushing against it, always looking for info, answers, help etc. Depressed people tend to somewhat “give up” and be depressed, until they’re not.

 

[Sean]

Same, I had a very good GP who explained that pwME are always trying, they’re always pushing against it, always looking for info, answers, help etc. Depressed people tend to somewhat “give up” and be depressed, until they’re not.

That certainly holds true for me. I have never stopped wanting to have a life, to be active and do stuff, from mundane practical daily tasks through to lofty life goals.

If we were just depressed we could not have got anywhere near as much done as we have via forums like this and other means.

One of the most remarkable and unacknowledged features about ME/CFS patients is our extraordinary psychological and moral resilience in holding up under such extreme adversity, with so little real hope, so much hostility and abuse and abandonment, and for so long, decades for many, lifetimes for some. Far from being pathetic weak little snowflakes we are models of perseverance and fortitude under extreme adversity.

How often do you see that being recognised and factored in by psychs?

 

[Kitty]

Same, I had a very good GP who explained that pwME are always trying, they’re always pushing against it, always looking for info, answers, help etc. Depressed people tend to somewhat “give up” and be depressed, until they’re not.

This is what baffles me about the confusion. Depression causes a kind of paralysis, where it can take people three or four days to make a brief phone call or order groceries, whereas everyone on this board talks about the endless struggle to avoid doing too much.

People with depression don't tend to talk about feeling ill, whereas people with ME/CFS usually feel ill the whole time.

To get back on topic, do we think genes associated with depression are just a common finding in GWAS, perhaps because there are quite a lot of them, or does there appear to be a real association here?

I don't think it's much of a concern if it is; having genetic changes linked to depression doesn't mean people are bound get it, any more than having changes linked to ME/CFS. Even where it does present, it's a condition in its own right and just one of a list of co-morbidities that may be present. Asthma, eczema, migraine or acne might be common too.

 

[MrMagoo]

People see what they want to see, at the end of the day the BPS crew will always find a way to word salad everything back to “they’re making themselves ill”.
When I worked, resilience was always lacking, apparently. Then when lockdown came and my job went and I was bedbound alone, guess what? Turns out I’m really resilient. And I was too ill to be working with sadists who deliberately made things difficult for me.