I haven't really been able to follow what exactly you're doing. Maybe you could lay out your overarching plan, and maybe describe what everything in one row of the table on this webpage means?
Genetics: Chromosome 1 NEGR1
- Thread starter Jonathan Edwards
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Will try to give a fuller writeup a go some other time when I’m up to it. But it’s basically just GenHancer info on promoters and enhancers (see the Genomics section on a GeneCards page) for DecodeME genes with links to view the locations on the DecodeME LocusZoom to see if they’re relevant.
Ah, ok, so the idea is, if there are significant hits near a gene, plus significant hits near multiple enhancers or promoters which encourage expression of that gene, it might be more likely to be relevant.
I just brushed up on the basics of what promoters and enhancers are with this video: Promoters and Enhancers
Yeah, it was meant to be a quick ‘oh this info on regulatory elements looks interesting, I wonder if I can knock something up to make it easy to link to and check if there are correlations to changes in the DecodeME data for the candidate genes, maybe it will tell us something’. And then got more complicated…
V.R.T.
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I think this is a really interesting connection to the PVN because the PVN apparantly mediates osmoregulation and so many pwME have issues with dehydration, excessive thirst, exessive and frequent urination (and sometimes in PEM the opposite - I need to drink loads but barely pee at all) etc. It seems like something is driving the fluid regulation of pwME haywire so this could be an important clue imo.
Osmoregulation stuck out to me:
'Osmoregulation is the active regulation of the osmotic pressure of an organism's body fluids, detected by osmoreceptors, to maintain the homeostasis of the organism's water content; that is, it maintains the fluid balance and the concentration of electrolytes (salts in solution which in this case is represented by body fluid) to keep the body fluids from becoming too diluted or concentrated.'
Osmoregulation - Wikipedia
en.wikipedia.org
If it was specifically the PVN, I think it'd be more interesting. But it seems like what you quoted is an AI mentioning PVN linking to NEGR1 because it's the area of interest that was asked about, while in reality NEGR1 may be involved everywhere in the brain. And if the question was about any other brain region, it'd say NEGR1 maintains the synaptic connections there too.
V.R.T.
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Oh right, my bad!
ME/CFS Science Blog
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Distance is usually measured to the transcription start site (TSS) of a gene, the place where the reading starts. Both genes are read in the <- direction so they are read from right to left and the TSS is on the right side of the gene.
For NEGR1 the TSS is 72,282,539
For LRRIQ3 the TSS is 74,198,176
Distance is usually measured to the most likely causal SNP which for DecodeME was the position of the lead SNP: 73,126,414.
None of the genes is close but NEGR1 (ca. 844 kb) is still a bit closer than LRRIQ3 (1,072 kb).
ME/CFS Science Blog
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My analysis didn't reveal much in this region. The credible set was large with 385 SNPs.
The eQTL didn't show any gene expression dataset with a similar signal (coloc PP.H4 > 0.8). The closest signal was a weak one for NEGR1 in the esophagus GTEx_v10 dataset (PP.H4 = 0.62, p-value 0.000039).
The phewas analysis also showed no similar signals in other GWAS except for sunburns (PP.H4 = 0.817). The many depression signals in this region didn't fully colocalize (The big Howard et al. 2019 study had a PP.H4 around 0.67). I think it's because the depression GWAS has two seperate signals here while ME/CFS has only one.
The chromatin data didn't clearly point to particular tissue although the strongest signals were for fetal (brain). Three SNPS from the credible set were in regulatory element EH38E2819238 which was more open there.
There were also no 3D-links to protein-coding genes in ENCODE. I tried to look further and found links between the credible region and NEGR1 in this dataset on pluripotent stem (iPS) cell-induced excitatory neurons. But I'm not very confident that this analysis is justified (or that I did it correctly). So don't take this too seriously.
So overall the locus doesn't give much insight but I think NEGR1 is the most likely causal gene and that the depression GWAS points to it as well.
The eQTL didn't show any gene expression dataset with a similar signal (coloc PP.H4 > 0.8). The closest signal was a weak one for NEGR1 in the esophagus GTEx_v10 dataset (PP.H4 = 0.62, p-value 0.000039).
The phewas analysis also showed no similar signals in other GWAS except for sunburns (PP.H4 = 0.817). The many depression signals in this region didn't fully colocalize (The big Howard et al. 2019 study had a PP.H4 around 0.67). I think it's because the depression GWAS has two seperate signals here while ME/CFS has only one.
The chromatin data didn't clearly point to particular tissue although the strongest signals were for fetal (brain). Three SNPS from the credible set were in regulatory element EH38E2819238 which was more open there.
There were also no 3D-links to protein-coding genes in ENCODE. I tried to look further and found links between the credible region and NEGR1 in this dataset on pluripotent stem (iPS) cell-induced excitatory neurons. But I'm not very confident that this analysis is justified (or that I did it correctly). So don't take this too seriously.
So overall the locus doesn't give much insight but I think NEGR1 is the most likely causal gene and that the depression GWAS points to it as well.
ME/CFS Science Blog
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Thought this was an interesting aspect of NEGR1. It reminded me of ARFGEF2 bringing GABA-A receptors to the cell surface.
Source: Neuronal growth regulator 1 (NEGR1) promotes synaptic targeting of glutamic acid decarboxylase 65 (GAD65) | bioRxiv
Sunburn is a curious thing that keeps coming back. I think you’d spotted it on chr. 20 as well. @ME/CFS Science Blog
Its interesting given that sometimes the symptoms after an activity feel a bit like sunburn.
Its interesting given that sometimes the symptoms after an activity feel a bit like sunburn.
ME/CFS Science Blog
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Here's what this plot looks like, it did not replicate in the Nott et al. dataset of neurons. More info about the datasets and methodology I used here.
The Hi-C data from 5 ENCODE brain samples show a different picture though. No special connection to NEGR1 but to ERICH3 and LRRC53.
So this region still looks ambiguous. Currently trying out this brain dataset but downloading it takes several hours:
Single-cell DNA methylation and 3D genome architecture in the human brain | Science
ME/CFS Science Blog
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Here's what it looks like, very similar to the ENCODE data and not supportive of NEGR1
The data file was too big we I sampled 2000 random nuclei for 7 major cell types: oligodendrocytes (ODC), VIP interneurons (Vip), D1 and D2 medium spiny neurons (MSN-D1, MSN-D2), L2/3 IT neurons (L2/3-IT), astrocytes (ASC) and microglia (MGC). Then I summed the contacts over 25kb bins and normalized them for the total contacts a bin has (similar to what ENCODEdoes in its datasets).
- Done with the help of AI.
ME/CFS Science Blog
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Another potential candidate here is ERICH3, a protein associated with cilium assembly but also neurotransmitter storage and vesicular trafficking in the brain.
ERICH3: vesicular association and antidepressant treatment response - PubMed
ERICH3: vesicular association and antidepressant treatment response - PubMed