Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

[Turtle]

Thanks. The more tempered statement is only relevant to the DecodeME GWAS result ("chr6p associated locus" containing several genes, including BTN2A1). The AstraZeneca result is specific to the gene: BTN2A1 has the significantly highest odds of disruptive rare DNA variants among pwME relative to people who do not have ME/CFS.
Yes, these genetic associations could be conferring risk mostly through increased susceptibility to infection (acute phase) rather than mechanisms acting subsequently.
What I find interesting about BTN2A1 is that it acts in innate immunity. Together with BTN3A1 it is a first-line sensor of bacterial presence, and it mediates the interaction with Vgamma9-Vdelta2 T-cells, which are "innate-like" lymphocytes.

Thanks for all your arduous work and taking the time to be part of s4me and explain all that complicated stuff.

Could that mean having EBV and pneumonia as the starting point of ME/CFS is a double whammy?
Obvious that I'm the opposite of a scientist.

 

[Verity]

I note that BTN2A1 variants confer risk for systemic lupus. That might be an important clue.

That's near the BTN2A1 locus for lupus and ME/CFS (not all genes shown). The ME/CFS locus is a little red hill on the left near the value 26.

It seems that for lupus, the main thing here is a gene farther to the right. Maybe an HLA gene. Though it's possible the BTN genes are also contributing to the significance towards the left

I don’t know enough to understand this image, but in case lupus is still potentially relevant at all, I just want to mention that a lot of people with SLE on the lupus subreddit report something that sounds very much like PEM, including symptoms you wouldn’t expect with regular exercise intolerance (e.g. iirc a significant delay and a sore throat). It seems like too many to be just chance overlap with ME.

I’ve done a little digging around on this because I have an “is it ME or is it something like lupus” situation going on myself.

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

 

[forestglip]

I note that BTN2A1 variants confer risk for systemic lupus. That might be an important clue.

Which study is this based on? I couldn't find it from a quick search.

 

[Jonathan Edwards]

Which study is this based on? I couldn't find it from a quick search.

Nor could I. AI is very unhelpful.
My impression is that the lupus linkage is so wide and complex that it is unlikely that the relatively local signal for ME/CFS is using the same risk mechanism.

 

[Nightsong]

I noticed that GeneCards had associated BTN2A1 with SLE (link). But if you follow the reference (ref 63), it comes from this page:

JensenLab - Literature associating BTN2A1 and systemic lupus erythematosus

The JensenLab tool is a database of gene/disease associations apparently based on automated text mining of papers. However, I'm not sure this is reliable - based on a few searches I don't see any SLE papers that report a specific association with BTN2A1, and the first few results from the database entry don't seem to make that specific link either, although many seem to mention BTN2A1 in other contexts.

 

[forestglip]

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

It certainly doesn't rule it out. It just doesn't provide good evidence for a connection.

 

[Jonathan Edwards]

Is there any possibility that BTN2A1 is binding to phospholipid in neurons or glia instead of bacterial phosphoantigens (which seem to be smaller sterols)?

As far as I can see BTN2A1 does not actually present the phosphoantigen to the T cell receptor but binds to the TCR if its cytoplasmic tail is bound by phosphoantigen.

 

[ScoutB]

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

No idea if it connects to this particular DecodeME locus, but that recent study comparing summary stats of DecodeMe to other GWAS said this:

Across adaptive and autoimmune traits, systemic lupus erythematosus (SLE) demonstrated the strongest association with ME/CFS (rg = 0.200, p = 1.15×10⁻¹⁰), with multiple sclerosis (MS) showing a smaller but consistent pattern.

Note that they only compared with 22 other traits (of which the adaptive and autoimmune ones were only a subset), so not sure how much weight to give this.

 

[Utsikt]

The findings of the present study extend knowledge of the role of BTN3A2 to a broader range of disorders. On the contrary, we found that BTN2A1 was associated with decreased risk of AD, anxiety, and SCZ, which is consistent with a report that BTN2A1 is involved in the immunomodulation of the activity of γδ T-cells and has significant anti-neuroinflammatory and neuroprotective effects51. Although BTN3A2 and BTN2A1 are known to interact52, given that BTN3A2 and BTN2A1 were separately identified as risk and protective factors for brain disorders in the present study, further studies are needed to elucidate the underlying mechanisms of how BTN3A2 and BTN2A1 proteins are oppositely involved in brain disorders.

BTN2A1 is protective for Alzheimer’s, anxiety and schizophrenia, according to this paper:

Atlas of proteomic signatures of brain structure and its links to brain disorders - Nature Communications

The connection between plasma proteomic and brain structure remains unclear. Here, the authors establish a comprehensive atlas of the patterns of associations between microscale proteome and brain structure, and demonstrate their potential value for studying brain disorders.

www.nature.com

51 is this:

Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More - PMC

Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively ...

pmc.ncbi.nlm.nih.gov

There also appears to be some ties to Coeliac disease:

BTN2A1 and BTN3A1 as Novel Coeliac Disease Risk Loci: An In Silico Analysis

Coeliac disease (CeD) is a gastrointestinal enteropathy triggered by the consumption of gluten in predisposed individuals. A recent study showed that individuals were at more than 10% risk of having CeD if a first-degree relative also had the disease. However, only around 50% of CeD genetic...

www.repository.cam.ac.uk

There might be some tissue data here, but I don’t have access:

https://academic.oup.com/jimmunol/article-abstract/179/6/3804/8022208

 

[Jonathan Edwards]

BTN2A1 is protective for Alzheimer’s, anxiety and schizophrenia, according to this paper:

Atlas of proteomic signatures of brain structure and its links to brain disorders - Nature Communications

The connection between plasma proteomic and brain structure remains unclear. Here, the authors establish a comprehensive atlas of the patterns of associations between microscale proteome and brain structure, and demonstrate their potential value for studying brain disorders.

www.nature.com

Is that a SNP-llnked variant of BTN2A1 that is protective, and is it associated with the risk SNP for ME/CFS? I am not sure how to interpret that.

 

[Utsikt]

Is that a SNP-llnked variant of BTN2A1 that is protective, and is it associated with the risk SNP for ME/CFS? I am not sure how to interpret that.

I have no clue, I’m just sharing stuff I found when searching for BTN2A1. I was hoping some of you guys would be able to understand it!

 

[Hutan]

Can someone with this stuff at their fingertips remind me:

So, there is a variant of a BTN gene associated SNP found to be enriched in the DecodeME sample - what gene does that affect and do we know with any certainty what impact the variant has on how the gene works? i.e. up or down regulation of a specific protein

Similarly with the BTN gene associated SNP found to be enriched in the UK Biobank sample - what gene does that affect and do we know with any certainty what impact the variant has on how the gene works?

Feel free to correct my question if necessary. and apologies for my laziness in not re-reading the thread to find the answers.

 

[forestglip]

Is that a SNP-llnked variant of BTN2A1 that is protective

It's mendelian randomization based, so they're doing something like looking at SNPs associated with expression of BTN2A1, and looking at the associations of those SNPs with disease in a different cohort to see if expression of the gene may be causal for the disease. And they found that increased expression of BTN2A1 may be protective against ALZ, schizophrenia, and anxiety.

I'm not sure if they give the specific SNPs they used to be able to check in the ME/CFS data. It's probably based on a collection of SNPs that all affect expression, so would probably require more in-depth analysis than just checking each one for an association anyway. I haven't read this thoroughly, though, so may have missed something.

This part looked interesting too:

the most notable finding being the association between increased BTN2A1 protein expression and lower [mean diffusivity] of the right parahippocampal part of the cingulum (beta = − 0.05, 95% CI − 0.08 to − 0.03, PFDR < 0.001).

 

[forestglip]

So, there is a variant of a BTN gene associated SNP found to be enriched in the DecodeME sample - what gene does that affect and do we know with any certainty what impact the variant has on how the gene works? i.e. up or down regulation of a specific protein

It's a significant variant on chromosome 6 with many genes in the area, so we can't be sure yet which gene it affects. DecodeME did not detect that the ME/CFS variant also affects expression of BTN2A1. (Though the risk allele was associated with decreased expression of BTN2A2.)

Similarly with the BTN gene associated SNP found to be enriched in the UK Biobank sample - what gene does that affect and do we know with any certainty what impact the variant has on how the gene works?

That study looked at how frequently rare variants within a given gene appear in ME/CFS vs controls. So it's based on potentially several different variants within a gene, not just one variant. And it looks like rare variants are seen in the BTN2A1 gene in ME/CFS more often than in controls. It might be possible to figure out what some of the specific variants do, though I don't know how to do that.

 

[Hutan]

Thanks @forestglip.

The possible association with BTN2A2 from DecodeME
What was the study that linked the reduced expression of BTNA2 with the risk allele? How reliable is it?

The UK Biobank finding of more rare variants of BTN2A1 in ME/CFS than controls
The increase in the number of rare variants in the ME/CFS group looked quite compelling. Seems to me though that finding out what the identified variants do in terms of up regulating or down regulating BTN2A1 would be very useful - both in the ME/CFS group and the controls. We also need to keep in mind the less than reliable diagnoses in that sample.

Of course, I understand that it's not always as simple as 'this variant produces that outcome'. There might be different outcomes with other genetic combinations, different outcomes at different life stages or in different environments.

 

[forestglip]

The association with BTN2A2 from DecodeME
What was the study that linked the reduced expression of BTNA2 with the risk allele? How reliable is it?

DecodeME. They tested whether there is a shared variant that is both associated with ME/CFS and with BTN2A2 expression. It's described in the candidate genes document.

The allele that increases the risk of ME/CFS is associated with decreasing BTN2A2 gene expression.

Another finding:

The allele that increases the risk of ME/CFS is associated with increased BTN3A3 expression in skin not exposed to the sun.

The UK Biobank finding of more rare variants of BTN2A1 in ME/CFS than controls
Seems to me that finding out what the identified variants do in terms of up regulating or down regulating BTN2A1 would be very useful - both in the ME/CFS group and the controls.

Of course, I understand that it's not always as simple as 'this variant produces that outcome'. There might be different outcomes with other genetic combinations, different outcomes at different life stages or in different environments.

Yes, and there are more possibilities than just increased/decreased expression. A variant might slightly change a protein's shape, affecting how it interacts with other proteins. So it could potentially be quite difficult to narrow down what exactly happens.

 

[ScoutB]

@forestglip @Hutan

I am too foggy at the moment to look into this properly but this wording by Chris:

anyone (who self-reported) ME or CFS had significantly more rare DNA variants that disrupted gene function in the BTN2A1 gene than expected (p = 2.4x10^-5), a level of significance greater than for all other protein-coding genes.

BTN2A1 has the significantly highest odds of disruptive rare DNA variants among pwME relative to people who do not have ME/CFS.

made me think that the AZ finding is that pwME are more likely to have variants that reduce BTN2A1's normal activity?

Also when I look at that link he sent for the AZ data, it looks like the search (in the 'model' field?) is broadly for various kinds of non-synonymous variants (says including protein-truncating variants, missense variants, in-frame insertions and deletions, splice acceptor variants and splice donor variants). I guess that is what is meant by disruptive.

So probably there's some uncertainty here but the idea is these variants would maybe be expected to result in less functional BTN2A1 protein on average? (agree with what you're saying forestglip about many other possibilities for each of them individually though.)

 

[Hutan]

DecodeME. They tested whether there is a shared variant that is both associated with ME/CFS and with BTN2A2 expression. It's described in the candidate genes document.

What I mean is, what study found that that variant is associated with reduced BTN2A2 expression? Obviously, we see a lot of rubbish papers and sometimes, poking into the details, we see that it's not reasonable to draw the headline conclusion.

 

[forestglip]

So probably there's some uncertainty here but the idea is these variants would maybe be expected to result in less functional BTN2A1 protein on average?

It looks like that most significant result for BTN2A1 is based on the "raredmgmtr" model, which is defined as including variants that are:

• Missense variants
• Predicted to be damaging (REVEL score ≥ 0.25)
• Rare (minor allele frequency ≤ 0.00025 within the cohort and ≤ 0.00005 within gnomAD)
• Missense variants must fall within a constrained region (MTR < 0.78 or MTR_centile < 0.5)

The REVEL paper says:

We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants

So I'm not sure these variants are necessarily making the protein less functional. I would think that a missense variant could make a protein become even more active, with the variant fulfilling these criteria.

 

[forestglip]

What I mean is, what study found that that variant is associated with reduced BTN2A2? Obviously, we see a lot of rubbish papers and sometimes, poking into the details, we see that it's not reasonable to draw the headline conclusion.

The GTEx project which is a very large study (in terms of funding and influence, but also sample size) meant to determine which variants are associated with gene expression. So probably fairly reliable.