Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders, 2021, Eijsbout

Andy

Andy

Retired committee member
Abstract

Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS.

Open access, https://www.nature.com/articles/s41588-021-00950-8
 
The paper said:
Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms.
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That's because for decades millions of people with IBS have been labeled with anxiety and depression. This is the literal basis for the belief that anxiety can cause those symptoms. They are simply unnecessary labels that made medicine waste decades on nonsense.

Given that GI health is so heavily dependent on its microbiome, I have no idea what allusions to the "gut-brain axis" even make sense here. It's just superfluous fluff.
 
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rvallee said:
That's because for decades millions of people with IBS have been labeled with anxiety and depression. This is the literal basis for the belief that anxiety can cause those symptoms.
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I think this may be a key point. What is probably more interesting is what mechanisms the genes are involved in. For example NCAM1:NCAM1 neural cell adhesion molecule 1 [Homo sapiens (human)] - Gene - NCBI (nih.gov)
This gene encodes a cell adhesion protein which is a member of the immunoglobulin superfamily. The encoded protein is involved in cell-to-cell interactions as well as cell-matrix interactions during development and differentiation. The encoded protein plays a role in the development of the nervous system by regulating neurogenesis, neurite outgrowth, and cell migration. This protein is also involved in the expansion of T lymphocytes, B lymphocytes and natural killer (NK) cells which play an important role in immune surveillance. This protein plays a role in signal transduction by interacting with fibroblast growth factor receptors, N-cadherin and other components of the extracellular matrix and by triggering signalling cascades involving FYN-focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K). One prominent isoform of this gene, cell surface molecule CD56, plays a role in several myeloproliferative disorders such as acute myeloid leukemia and differential expression of this gene is associated with differential disease progression. For example, increased expression of CD56 is correlated with lower survival in acute myeloid leukemia patients whereas increased severity of COVID-19 is correlated with decreased abundance of CD56-expressing NK cells in peripheral blood. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Aug 2020]
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It looks as if the UK Biobank data replicated findings from 23&Me? But yes, there is a problem here.

If these genes not turn up for ME/CFS that might be something very important.
A link to anxiety is pretty much bound to occur with 'IBS'. I suspect almost anyone with significant anxiety problems can pick up a diagnosis of IBS since most of us have gut problems of one sort or another (all my family do).

But ME might not fall prey to that. Even if there appears to be overlap between ME and IBS, it might still be that ME itself does not segregate with these genes (if the association with IBS is real).

And the suggestion in the paper that NCAM might be relevant independently to anxiety and IBS is also an interesting possibility. NCAM would certainly be a plausible candidate to link with a neural signalling problem - and it has immunological relevance too.
 
Dolphin said:
Might there be a selection bias in terms of the people who took part i.e. the sample may not be representative of those who have the condition, diagnosed or undiagnosed, in society?
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While there might be selection bias, it shows that there is a certain number of people who have this which is an interesting fact. The bias means it is impossible to say if it happens in all cases of IBS or just a small proportion but it is possible to say it can happen.

If you ask people if they get an allergic reaction to pineapple you would expect a bias towards people who have the allergy but it still shows that the allergy exists.
 
Mithriel said:
While there might be selection bias, it shows that there is a certain number of people who have this which is an interesting fact. The bias means it is impossible to say if it happens in all cases of IBS or just a small proportion but it is possible to say it can happen.
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I am not sure what you are meaning here and the analogy with allergy does not seem quite relevant.

What are being looked for are gene variants. If these gene variants are more common in people with anxiety and people with anxiety are more likely to report IBS then any apparent link between the gene and IBS is spurious. The gene variants will be present in some people throughout the population and in nearly all cases of no relevance to anything. So we have to very careful about deducing that they have anything to do with IBS.

If I was an anxious type I would probably have got a diagnosis of IBS by now. I have a diagnosis of functional bowel disorder as it is but I ignore it. I suspect almost anyone can collect a diagnosis of IBS if they complain enough about repeated abdominal pain, which most of us get at some time.
 
I see what you mean. I am wary of this argument because of the way that the BPS dismissed reports of harm in ME from GET by saying it was a biased selection of responders when it does not matter if it is 500 from 1000 or 500 from 50000 it is still a large number.

The possibility of a link is exciting though. If we can keep the psychologists out of it, genetics, biology and the interaction with health have discoveries coming at a great rate.
 
Jonathan Edwards said:
It looks as if the UK Biobank data replicated findings from 23&Me? But yes, there is a problem here.

If these genes not turn up for ME/CFS that might be something very important.
A link to anxiety is pretty much bound to occur with 'IBS'. I suspect almost anyone with significant anxiety problems can pick up a diagnosis of IBS since most of us have gut problems of one sort or another (all my family do).

But ME might not fall prey to that. Even if there appears to be overlap between ME and IBS, it might still be that ME itself does not segregate with these genes (if the association with IBS is real).

And the suggestion in the paper that NCAM might be relevant independently to anxiety and IBS is also an interesting possibility. NCAM would certainly be a plausible candidate to link with a neural signalling problem - and it has immunological relevance too.
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So what you are saying is that the genes could be part of the IBS or and ME and it is the gut brain barrier that causes the anxiety or 101 other interactions in the systems that impact mood.

One of those impacts include; for me anyhow my 'bad mood syndrome' is not enough coffee. I wonder if they have found the gene for it yet; the need for coffee to stay in a state of utopia and calmness. I know that this is not the normal response to coffee people get but it is my salvation.

Your last sentence is where the focus should be, and I for one are now a little bit hopeful we are a tiny bit further forward. Now having a coffee to celebrate :party::emoji_coffee::emoji_coffee::emoji_coffee::emoji_coffee::emoji_coffee:
 
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