When would a GWAS study help disprove the belief that ME/CFS is psychological

From what I’ve understood the strengths of a GWAS study is that it reflects causes rather than effects of an illness as genes don’t change after ME onset. At what point can one conclude that a cause seems to be biological?

From what I can see there have been several studies on conditions typically believed to be mainly psychological that have found risk genes. I can imagine there might be several reasons for this and the condition still being viewed as psychological. There might be certain biases in a GWAS, for instance if there was a certain phenomena in a region causing psychological distress and the genes picked up in a GWAS are because people from that region have a different genetic makeup to the rest of the population (this might seem irrelevant if you have controls that are from the same region, but there are likely other biases correlated with different social factors, be it race or regions with a higher prevalence of doctors diagnosing a condition etc). Similarly conditions such as depression or schizophrenia are cited to have a genetic component.

Of course there’s the possibility that a gene pops out that directly makes physiological sense, for example a link to something that is related to exertion or related to tissue inflammation. There’s also the possibility that genes pop out that are commonly related to autoimmune diseases, which might make it more likely that ME/CFS is an autoimmune disease, but what happens if genes that are also related to something like depression show up?

 

What should happen is that it will improve the understanding of the biological cause of both ME/CFS and depression.


Causal role of immune cells in major depressive disorder and bipolar disorder: Mendelian randomization MR study (2024, Journal of Affective Disorders)

Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression (2024, Brain, Behavior, and Immunity)

A mitochondrial nexus in major depressive disorder: Integration with the psycho-immune-neuroendocrine network (2024, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease)

Association between mitochondrial DNA levels and depression: a systematic review and meta-analysis (2023, BMC Psychiatry)

Mitochondrial dysfunction: A fatal blow in depression (2023, Biomedicine & Pharmacotherapy)

Mitochondria-wide association study observed significant interactions of mitochondrial respiratory and the inflammatory in the development of anxiety and depression (2023, Nature Translational Psychiatry)

Connecting Dots between Mitochondrial Dysfunction and Depression (2023, Biomolecules)

Predicting depression risk in early adolescence via multimodal brain imaging (2024, NeuroImage: Clinical)

Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety (2024, Nature Medicine)

 

I think it is important to distinguish 'psychological' from 'psychiatric' or indeed 'involving thinking'.

Depressive illness is not psychological, nor is schizophrenia, or Alzheimer's or Parkinson's or bipolar disorder. At least it is not psychological in the sense that everyone wants to avoid.

'Psychological' in the sense that people object to is by definition not genetic. It means that an illness is caused by ideas. That turns out to be a fairly incoherent conception but then the psychodynamic side of psychiatry is pretty incoherent and folklore tends to be too.

In simple terms the psychological theory is that there is nothing wrong other than the idea that something is wrong. And that there is no internal underlying cause for having that idea other than the idea itself. So someone with persistent depression does not have a psychological illness if it turns out that their ideas of worthlessness are a knock on effect of an allele of a serotonin receptor gene.

I don't think there is any real need to be worried about this. The GWAS study may show that people with ME/CFS are more likely to have unusual alleles of a TWEAK6 gene that mediates an interaction between sensory neurone and gamma interferon which sets up a spiral of negative signalling that completely take over the sensorium despite metabolic pathways being entirely normal. That might ultimately prove that the disease is 'all in the head' or at least 'all in the nervous system' but that wouldn't matter. It would be great. Someone could synthesise a TWEAK6 agonist and people with ME/CFS could be restored to a normal life.

 

This is a great question, one that I’ve also grappled with. All of the main psychiatric conditions listed in the DSM (MDD, BPAD, schizophrenia, autism, various dementias etc.) are heritable, including the ones you wouldn’t necessarily expect based on folk beliefs/misunderstanding of the world, like PTSD and addictions. Most of the top psychiatry journals predominantly publish genetic stuff these days. The BPS stuff appears mostly in fringe psychosomatic journals. None of the biological discoveries in psychiatry have led to these conditions being treated like normal medical disorders. It seems that anything that primarily manifests itself as a behavioural or thinking problem will get stigmatised and othered no matter the cause.

GWAS isn’t going to help us politically in any way, unless the genes identified act primarily on some system outside of the brain. If anything relating to HPA axis/stress response or the monoaminergic systems is identified, it will only serve to destroy us further. So I urge people to be extremely cautious with stuff like DecodeME and not get their hopes up.

 

The line between psychiatric and neurological seems extremely arbitrary.

 

No one can articulate it clearly. It usually boils down to there being two broad types of brain rot: focal signs go to neurology and the rest gets carted off to psychiatry.

 

Best case scenario we get something that's immediately targetable with biologics; worst case scenario is if nothing achieves significance and we're no better off, but even if the classical GWAS approach doesn't yield any results then there are other approaches that might and it seems they have already shared some of their samples with an outside genomics company to trial a different approach. We might get something that no-one really knows what to do with like an association with an integrin or ring-finger protein gene like those found in a GWAS of chronic widespread pain. If it shows up associations with genes associated with catecholamine metabolism or the serotonin or dopamine transporter genes then it may inspire a number of speculative BPS papers and tweets but nonetheless we'll learn more about the biology in a way that is independent of anyone's preconceptions.

Some GWASes seem to have shown interesting results that don't seem to have shifted an established field very much - looking at various studies I see there was a decent sized GWAS showing both metabolic and neuronal contributions to anorexia nervosa; a library search tells me that the metabolic contributions don't seem to have been the subject of much investigation. Also sometimes a GWAS confirms previous theories: I recall that there there were historically two leading causal theories for migraine - the vascular theory and the theory that it was a disorder of neurotransmitter function - and when well powered GWASes for migraine started to happen it turned out that there were contributions from both.

 

And because the symbolism is too delicious: it's basically a problem of resolution, making the line seem to disappear. In addition to problems of compression, so much JPEGging.

Can't see the line at 10x, doesn't exist. Can't see the line at 100x, doesn't exist. Oh lookie here, a line is clearly visible at 1000x, who could have known? Basically the equivalent of this. In the end, only technology matters. Where technology fails, it's up to human judgment alone, and that almost never works.



Early images of Mars seemed to show a face. Turns out it was shadows. Turns out it wasn't even shadows, it was just poor resolution creating visual artefacts.

 

Psychiatry/psychology does seem similar to ancient Greek mythology. They could make up an eagle/lion creature, and no one at the time could prove that it wasn't possible. If someone complained that aside from a few anecdotal reports, no one had seen one, the creator could have added a magic ability to hide. Is psychiatry/psychology still in the ancient Greek level of science?

 

Jonathan.. You’ve mentioned this hypothetical scenario twice.. is this a hint at an early finding?

 

If it is I can't remember where I read it!! It just sounded a good name for a molecule.
I am not at liberty to discuss what I read in applications but I have seen some interesting things recently. There are people with good skills and facilities getting involved. In the last six months I have seen two really good novel ideas about how to gather information. We are no longer in a situation in which people who know what they are doing are just not involved. They are. Long Covid has had an impact but it was happening anyway.

 

Cue that old chestnut :


‘The name hysteria is derived from the Greek word hystera which means uterus. In the earliest known treatise dealing with the complaint—Kahun papyrus dating from about 1900 BC—it is attributed to starvation or displacement of the uterus. This theory is repeated by Hippocrates, Plato, Celsus, Arataeus, and Soranus…’

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/488986#:~:text=The name hysteria is derived,Celsus, Arataeus, and Soranus.

Hi
I’m new here thanks for having me.

Apologies my ability to communicate is very poor both physical and cognitive.

This is my first post but have learned much reading here before managing to register.

Kind regards

 

Nice to meet you! Welcome

 

See also thread from paper today Preferential and sustained platelet activation in COVID-19 survivors with mental disorders (2024, Nature Scientific Reports)

 

I wonder whether there's also an aspect of "telling the most entertaining tale". The better the story you come up with, the more pay and prestige you get. That's a problem that occurs when there aren't measurable results to base success on.

 

Many thanks for the warm welcome

 

Many thanks for the warm welcome