Genetics: Chromosome 6 FBXL4, POU3F2

Here are the results of my brief analysis of this locus (there's more about my methods and approach in the chr20 locus).

Credible set
This region also had one credible set of 86 SNPs over a 180 kb. It’s in a gene desert, far removed from protein coding genes but lies in a long non-coding RNA called ENSG00000271860. It also includes another non-coding RNA called MIR2113.

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Chromatin
5 of the SNPS were in a regulatory region suggesting open chromatin. The biggest effects for DNAse results were for regulatory region EH38E4411500 which contains rs756671264. The chromatin here was most open in fetal brain samples.

Another one of these regulatory regions (EH38E2487665 containing rs7753937) had 3D contacts with promotor region of several genes. POU3F2 was the only protein-coding gene. Data came from Intact Hi-C in mammary epithelial cells (MCF 10A) though, not from brain samples.

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eQTL
In the more than 200 eQTL datasets I only found one with a high probability of having the same signal and it was a weak one linked with the non-coding RNA in the brain/amygdala. The ME/CFS risk allele lowers the IncRNA.

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Phewas
In the Phewas analysis of other genetic studies that found a similar signal here I got peculiar results. The large analyses BMI and intelligence signals in this region give PP. H3 0.8-0.99 which suggests that their main signals are driven by different variants. There were multiple dataset that had a similar signal but I can’t really make much sense out of the results. There doesn't seem to be a clear pattern.

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It looks like these are analyses from the the UK biobank dataset. Perhaps it points to some participation bias in the UK biobank or perhaps it’s just noise from scanning 50,000 GWAS looking for a signal. Plotting the data shows that the signal is often a bit different despite the high colocalization.

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The prioritzation of FBXL4 in the preprint seems to be mostly based on it being the closest gene. But it is not really close and the 3D chromatin data suggested a link with POU3F2 which is also the strongest brain-based protein coding gene nearby.

So my guess for this locus is that it points to an effect from POU3F2, possibly during fetal development. It is involved in how cortical neurons are wired but perhaps more interesting is its potential link to the hypothalamus and CRH: “POU3F2 encodes a POU domain transcription factor that acts in neuronal differentiation and activates corticotropin-releasing hormone regulated genes.”
https://www.genecards.org/card/POU3F2
 
“POU3F2 encodes a POU domain transcription factor that acts in neuronal differentiation and activates corticotropin-releasing hormone regulated genes.”

I like it.
I am all for taking note when amongst the utter confusion a jumble of letters pops up that supports a favourite scent, and ignoring it if it supports a spit-back. ;)
(Having spent the last few hours trying to piece together what all these hypothalamic mediators might be saying to each other.)
 
I agree, I think POU3F2 makes more sense.

This paper says that POU3F2 expression increases substantially in schizophrenia, though GWAS hits for schizophrenia didn't obviously point to it. It speculated in the discussion that some of the schizophrenia GWAS hits may be explained by variants in regulatory regions of POU3F2's downstream target genes, potentially making them less POU3F2-responsive.

Here the story seems to be a little different--the issue in ME/CFS might be whether/how much POU3F2 itself is responsive to something else that acts within that big regulatory region.
 
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I couldnt quite parse if this is just during foetal development?
So the finding that BRN2 activates CRH transcription is in-vitro, not necessarily limited to fetal development. Though what they're showing in fetuses is that if you knock out BRN2 the mice don't have detectable CRH production in neurons (besides a rare few that get driven by BRN4). What they didn't show is whether BRN2 is required for all CRH transcription even after fetal development.
 
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