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

[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.

 

[forestglip]

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)?

Here are all the items (only from UK Biobank analysis) which contain the text "depres" and which were Bonferroni significantly correlated with ME/CFS, with links to descriptions of the items, in order of correlation with highest at the top. The last item is negatively correlated.

The most correlated item, for example, refers to being diagnosed by a "professional". The webpage shows a screenshot of the question which includes "By professional we mean: any doctor, nurse or person with specialist training (such as a psychologist or therapist)."

• Mental health problems ever diagnosed by a professional: Depression
• Illnesses of siblings: Severe depression
• Substances taken for depression: Medication prescribed to you (for at least two weeks)
• Impact on normal roles during worst period of depression
• Bipolar and major depression status: Probable Recurrent major depression (severe)
• Seen doctor (GP) for nerves, anxiety, tension or depression
• Fraction of day affected during worst episode of depression
• Non-cancer illness code, self-reported: depression
• Illnesses of mother: Severe depression
• Seen a psychiatrist for nerves, anxiety, tension or depression
• Ever had prolonged feelings of sadness or depression
• Professional informed about depression
• Difficulty concentrating during worst depression
• Recent feelings of depression
• Ever depressed for a whole week
• Bipolar and major depression status: Probable Recurrent major depression (moderate)
• Activities undertaken to treat depression: Other therapeutic activities such as mindfulness, yoga or art classes
• Frequency of depressed mood in last 2 weeks
• Activities undertaken to treat depression: Talking therapies, such as psychotherapy, counselling, group therapy or CBT
• Substances taken for depression: Drugs or alcohol (more than once)
• Bipolar and major depression status: No Bipolar or Depression

 

[mariovitali]

Speaking of depression I wonder if questionnaires used, specifically asked whether episodes of depression occurred before MECFS and not after getting it.

 

[Turtle]

The best question to ask is.
What would want to do if you were cured?
A pwME/CFS would come up with a 50 items bucket list
A depressed person would come up with: I don't know

 

[EndME]

The DecodeME questionnaires are available online, here and here (@Andy I also used to be able to find them on the DecodeME website, for example here, but the links seem to have stopped working). I think it is fair to say that they've collected all the information people were asking about.

The questions on depression I found are the following:

• "If a health professional has ever told you that you had any of the conditions below, please select all that apply" "Clinical depression" (Tick active or not active)
• "During the past 6 months have you had any of the following symptoms?" "Depression" (Tick yes, no or prefer not to answer)
• Then there is a specific "Depression and Anxiety" section asking questions about specific symptoms (I have not listed those questions)
• "Did you experience prolonged periods of low mood or were diagnosed with depression before you had ME/CFS?"
  •  Yes, I experienced periods of low mood but wasn't diagnosed with depression
  •  Yes, I was diagnosed with depression
  •  No
• "Have you experienced prolonged periods of low mood or have been diagnosed with depression after your ME/CFS began?"
  • Yes, I experienced periods of low mood but haven’t been diagnosed with depression
  • Yes, I was diagnosed with depression
  • No (Skip to Question 27)
• "Please select which of the following applies to you:"
  •  The main reason for my low mood/depression is the impact that ME/CFS has
    on my life
  •  Other issues than ME/CFS are the main reason for my low mood/depression
  •  I’m not sure what is the main reason for my low mood/depression
• "Did you experience prolonged periods of feeling anxious or were diagnosed with generalised anxiety disorder before you had ME/CFS?"
  •  Yes, I experienced periods of feeling anxious but wasn't diagnosed with anxiety
  •  Yes, I was diagnosed with generalised anxiety disorder
  •  No
• "Have you experienced prolonged periods of feeling anxious or were diagnosed with generalised anxiety disorder after your ME/CFS began?"
  •  Yes, I experienced periods of feeling anxious but haven’t been diagnosed with anxiety
  •  Yes, I was diagnosed with generalised anxiety disorder
  •  No (Skip to Question 29)
• "Please select which of the following applies to you:"
  •  The main reason for my anxiety is my ME/CFS (the symptoms and impact of
    the illness on my life)
  •  ME/CFS is not the main reason for my anxiety although it may still impact the
    way I feel
  •  I'm unsure if my ME/CFS is the main reason for my anxiety or not

 

[EndME]

Also note: Certain (including psychiatric) conditions made you ineligible to participate in DecodeME. I don't know how that pertains to depression pre ME/CFS.

 

[Andy]

(@Andy I also used to be able to find them on the DecodeME website, for example here, but the links seem to have stopped working)

As you have found the DecodeME website is now part of the University of Edinburgh website here, and all previous content can be found there. There is a redirect set on decodeme.org,uk to take visitors to the new site but it looks like this does not seem to apply to other pages on the old site.

 

[Kitty]

Here are all the items (only from UK Biobank analysis) which contain the text "depres" and which were Bonferroni significantly correlated with ME/CFS, with links to descriptions of the items, in order of correlation with highest at the top.

Does anyone else think some items on that list look a bit...absurd?

Feeling depressed for a whole week
That would draw in a goodly proportion of perfectly healthy women with premenstrual syndrome, who aren't depressed according to the clinical understanding of the term and wouldn't be treated for depression by any sensible doctor.

Seen doctor (GP) for nerves, anxiety, tension or depression
Ever had prolonged feelings of sadness or depression
Professional informed about depression
These would include people suffering from grief, stress at work, family problems, and undiagnosed conditions that doctors assume are depression by default. None of them necessarily are depression.

If you change the word "depression" in those questions to "rash" or "cough" or "backache" it looks over the top to begin with, and then a bit sinister. As if you're being interrogated for even the faintest signs of recusancy or something.

 

[Utsikt]

Here are all the items (only from UK Biobank analysis) which contain the text "depres" and which were Bonferroni significantly correlated with ME/CFS, with links to descriptions of the items, in order of correlation with highest at the top. The last item is negatively correlated.

The most correlated item, for example, refers to being diagnosed by a "professional". The webpage shows a screenshot of the question which includes "By professional we mean: any doctor, nurse or person with specialist training (such as a psychologist or therapist)."

Thank you!

It seems like there are a lot of ways for any ill person to be labelled with depression.

And if it only asks for having ever ticked off one of those boxes, the gene might as well be considered a «general unwellness» gene. It might even be a «woman feeling unwell» gene with all we know about the bias against women in healthcare.

 

[rvallee]

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?

Never. It's been one of the most harmful lies about us. We are as strong a testament to human resilience as it gets, and we have literally been cast aside for "not trying". I hate this lie so much. The liars who say these things about us know nothing about us.

It's even well-documented enough, except evidence barely matters, only perception and politics. As textbook as "blaming the victim" ever gets.

 

[V.R.T.]

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.

This. Precisely this. Even if we never get justice for what has been done to us, I hope one day we get to a point where our resilliance is at least acknowledged.

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

Is this true? I am genuinely asking, I began to feel unwell at the same time as getting depression and was told it was very common for pw depression to feel unwell. And I have non MECFS (afaik) friends who have been told the same.

Speaking of depression I wonder if questionnaires used, specifically asked whether episodes of depression occurred before MECFS and not after getting it.

My depression appeared before my ME/CFS. It may well have been part of a prodromal onset as I got a lot of other odd neuropsychiatric symptoms at that time but I was undoubtedly depressed.

The best question to ask is.
What would want to do if you were cured?
A pwME/CFS would come up with a 50 items bucket list
A depressed person would come up with: I don't know

I think the truth is a little more complicated than this, though broadly along the same lines. I still had dreams and ambitions when I was depressed but I couldn't effectively work towards them.

So I might still have said that if my mental health issues were cured I'd start gigging again, or travel. But right now I could give you a long list of all the places I'd travel to, or all the musical projects I'd start right down to what instruments I'd use, recording techniques etc. And those details were the things that were hard to visualise when i was depressed.



FWIW I was a DecodeME participant but they initally declined me, then invited me during the second batch of recruitment.

 

[Kitty]

Is this true? I am genuinely asking

I'm not a sufferer so I can't really know, but none of the depression-prone people I've known and worked with ever complained about having the 'flu-like symptoms, pain, and crippling orthostatic intolerance that characterise ME/CFS. You don't tend to see them in descriptions of depression symptoms either.

Depression is multifaceted, but you'd think ME/CFS and PEM symptoms would be distinctive enough to be separated from it. Perhaps not in a single consultation with a newly ill patient bewildered by a whole array of bizarre symptoms, but that's true of many conditions.

 

[Verity]

I'm not a sufferer so I can't really know, but none of the depression-prone people I've known and worked with ever complained about having the 'flu-like symptoms, pain, and crippling orthostatic intolerance that characterise ME/CFS. You don't tend to see them in descriptions of depression symptoms either.

This sounds right to me, as someone who has had depression. I wouldn’t be surprised if it could cause some mild aches, but I doubt it would be anything on the level of ME.