Genetics: locus 6:4,336,259 - gene CDYL

[ME/CFS Science Blog]

Another DecodeME hit that remained just below the significance threshold (p = 2.9 × 10⁻⁷).
The T risk allele was present in 81.9% of cases and 79.3% in controls, resulting in an odds ratio of 1.086 per copy of T.

The 95% credible set using SUSIE consists of 22 SNPs that lie in the RNA ENSG00000284823 (antisense to CDYL) but protein coding genes are far away.




This is one of the areas where data on 3-D folding of the DNA is useful because the Hi-C domains show that the signal almost only includes CYDL on the east side as protein-coding gene. So I think this is the most likely candidate for this region.

 

[ME/CFS Science Blog]

Gene card:

CDYL encodes a chromatin reader and crotonyl-CoA hydratase that links histone mark recognition to transcriptional repression. The protein binds H3K9me3 and H3K27me3 to help maintain repressive chromatin architecture, and it functions in a regulatory pathway that supports gene silencing programs.

Through its chromodomain, CDYL promotes PRC2 activity and recruits EHMT2 to reinforce H3K9 dimethylation, while its crotonase-like activity converts crotonyl-CoA to β-hydroxybutyryl-CoA and suppresses histone crotonylation. These activities contribute to X-inactivation, neuronal gene silencing, and DNA repair. CDYL is localized to the chromosome, nucleus, nuclear speck, and cytoplasm, and expression is high in brain, endocrine system, and respiratory system tissues.

Clinically, CDYL has been implicated in infertility through a primate-specific Y-chromosomal gene family arising from this autosomal gene. Pathogenic relevance is also tied to its role in neuronal gene silencing and DNA repair. The protein is widely expressed across tissues, including female reproductive, hematopoietic, eye, skin, and cardiovascular systems.

CDYL Gene - GeneCards

 

[ME/CFS Science Blog]

The eqtl didn't found any notable results while the phewas found two other genetic studies with a similar signal:

Trait	PP.H4	lead_p	study_ID	Source
Gastro-oesophageal reflux disease	0.97	1.3e-05	finn-b-K11_REFLUX	OpenGWAS
rfMRI amplitudes (ICA100 node 51)	0.90	5.7e-06	ubm-b-2214	OpenGWAS

 

[ME/CFS Science Blog]

Looks like CDYL is a gene that keeps nerve cells from becoming over-excitable. Knock-out models in mice have been linked to epilepsy and pain.

Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. [....] Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility,

CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression - PMC

Here it is reported that the epigenetic factor chromodomain Y-like (CDYL) is crucial for pain processing. Selective knockout of CDYL in sensory neurons results in decreased neuronal excitability and nociception.

Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons - PubMed

 

[V.R.T.]

Looks like CDYL is a gene that keeps nerve cells from becoming over-excitable. Knock-out models in mice have been linked to epilepsy and pain.

CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression - PMC


Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons - PubMed

This looks important - did people with MECFS have less of this gene, or was it associated with decreased risk? I can't quite remember how it works in GWAS right now but what I'm getting at is - was the association in the right direction for this effect to be relevant?

 

[ME/CFS Science Blog]

did people with MECFS have less of this gene, or was it associated with decreased risk? I can't quite remember how it works in GWAS right now but was the association in the right direction for this effect to be relevant?

Hard to say because we have no dataset on gene expression that matches (the eqtl section). So Decode shows which versions of the DNA are more common in people with ME/CFS but not if a gene expression is increased or decreased.

 

[ME/CFS Science Blog]

@James Cox Perhaps this region is of interest to you.