Genetics: locus 2: 57,808,420 - genes VRK2, FANCL

[ME/CFS Science Blog]

This signal that was just below the significance threshold (9.5 × 10⁻⁷) in DecodeME. The risk allele frequency was 64.4% in cases, 62.9% in controls.

SUSIE's finemapping found two independent signals for this locus. One is largely inside the gene VRK2 gene. The other lies a bit more to the east, inside the non-coding RNA LINC01122. The first credible set includes the promotor of VRK2 and FLAMES also picks VRK2 so I think this is the most likely candidate. The only other protein-coding gene nearby is FANCL.



Here are the results of the eQTL, where both FANCL and VRK2 both appears but not with a really good match

Trait (gene)	Study	PP.H4	lead_p	risk_allele
ENSG00000287875 (signal 1)	GTEx_v10 | testis | naive | QTD000336	0.85	1.5e-06	lowers (z = -4.7)
FANCL (signal 1)	GTEx_v10 | brain (cerebellum) | naive | QTD000166	0.83	4.8e-07	lowers (z = -4.3)
ENSG00000285755 (signal 1)	CommonMind | brain (DLPFC) | naive | QTD000075	0.83	3.4e-06	raises (z = 3.5)
VRK2 (signal 2)	GTEx_v10 | tibial nerve | naive | QTD000286	0.81	7.7e-07	lowers (z = -3.9)
FANCL (signal 1)	GTEx_v10 | skin (suprapubic) | naive | QTD000311	0.77	1.9e-07	raises (z = 3.2)
EIF3FP3 (signal 1)	Cytoimmgen_reannotated | regulatory T cell | anti-CD3-CD28_5D | QTD000906	0.54	1.6e-04	lowers (z = -3.2)
ENSG00000287875 (signal 1)	IBDverse | memory B cell | naive | QTD000831	0.50	2.6e-04	raises (z = 2.8)
VRK2 (signal 2)	GTEx_v10 | spleen | naive | QTD000326	0.49	2.2e-04	lowers (z = -3.5)
ENSG00000285755 (signal 1)	OneK1K_reannotated | naive B cell | naive | QTD000887	0.46	3.2e-04	lowers (z = -2.8)
VRK2 (signal 2)	GTEx_v10 | brain (spinal cord) | naive | QTD000201	0.45	3.6e-07	lowers (z = -3.4)
ENSG00000287875 (signal 2)	IBDverse | memory B cell | naive | QTD000831	0.42	1.3e-04	raises (z = 2.5)
VRK2 (signal 1)	Perez_2022_reannotated | MAIT cell | naive | QTD000868	0.37	4.6e-04	raises (z = 3.1)
FANCL (signal 1)	GTEx_v10 | brain (cerebellum) | naive | QTD000161	0.36	4.0e-04	lowers (z = -2.5)
VRK2 (signal 2)	GTEx_v10 | adrenal gland | naive | QTD000126	0.35	6.6e-04	lowers (z = -3.4)

In the phewas there were many other 138 genetic datasets with PP.H4, so quite a lot. Sleep duration had the most similar signal.

 

[ME/CFS Science Blog]

In the phewas there were many other 138 genetic datasets with PP.H4, so quite a lot. Sleep duration had the most similar signal.

This list also includes:

- Frequency of tiredness / lethargy in last 2 weeks 0.849 4.66e- 7 OpenGWAS ukb-a-245
- Schizophrenia 0.847 4.28e-16 OpenGWAS ieu-b-5102

 

[ME/CFS Science Blog]

The gene card for VRK2

VRK2 encodes a serine/threonine kinase that functions as an effector of signaling pathways regulating apoptosis and tumor cell growth. It belongs to the vaccinia-related kinase family and is widely expressed, with protein and RNA expression reported in hematopoietic system, pancreas, brain, connective tissue, female reproductive system, and cardiovascular system. The protein localizes to the cytoplasm, endoplasmic reticulum membrane, mitochondrial membrane, and nucleus.

VRK2 modulates JNK and ERK signaling by disrupting MAPK8IP1-MAPK complex assembly and inhibiting ERBB2- and HRAS-driven pathways. It also enhances p53 stability and activity through phosphorylation of Thr-18, reduction of MDM2-mediated ubiquitination, and promotion of EP300-dependent acetylation. These activities place VRK2 in signal transduction, transcriptional control, and cell cycle-related pathways.

Clinically, variants in VRK2 have been associated with schizophrenia, and the gene is also linked to epilepsy. Alternative splicing produces multiple transcript variants with different subcellular localization and biological activity. Together, these findings place VRK2 among genes studied in neuropsychiatric and neurological disease contexts.

VRK2 Gene - GeneCards

 

[fst]

The gene card for VRK2

VRK2 Gene - GeneCards

I'm under the impression that almost all of these genes you dug out in the last days relate in some way or another to either to Glutamate/GABA or some synaptic function.

VRK2 is maybe one of the less obvious cases but studies exist, e.g., here or here.

But it really seems like there's a common theme emerging. Really looking forward to your summary.