Genetics: locus 1: 181,676,091 - genes CACNA1E

[ME/CFS Science Blog]

Another DecodeME locus just below (p = 8.9 × 10⁻⁷) the significance threshold. The top hit is 1:181676091:G:A with a risk allele frequency of 31.5% in cases, 30.2% in controls.

This locus is useful because the credible set lies fully in the CACNA1E gene while other protein-genes are far away. FLAMES also estimates that CACNA1E is the causal gene here.



The eqtl didn't give a clear match but they suggest that CACNA1E might be increased in ME/CFS in the brain.

Trait (gene)	Study	PP.H4	lead_p	risk_allele
MR1	Quach_2016 | monocyte | naive | QTD000409	0.76	1.1e-05	lowers (z = -1.9)
ENSG00000272880	GTEx_v10 | brain (caudate) | naive | QTD000156	0.75	1.3e-05	lowers (z = -3.9)
CACNA1E	GTEx_v10 | brain (cerebellum) | naive | QTD000161	0.68	4.2e-07	raises (z = 3.2)
IER5	IBDverse | tissue-resident macrophage | naive | QTD000822	0.55	1.1e-04	lowers (z = -4.5)
LINC01686	GTEx_v10 | skin (suprapubic) | naive | QTD000311	0.53	9.1e-05	raises (z = 2.6)
CACNA1E [ILMN_1664047]	Fairfax_2014 | monocyte | LPS_24h | QTD000084	0.52	1.7e-04	raises (z = 3.5)
CACNA1E	GTEx_v10 | brain (cerebellum) | naive | QTD000166	0.51	1.1e-05	raises (z = 1.9)
STX6	GTEx_v10 | ovary | naive | QTD000291	0.47	3.4e-04	lowers (z = -3.6)
RGS16	GTEx_v10 | thyroid | naive | QTD000341	0.45	1.1e-03	lowers (z = -3.3)

And here were the other genetic studies that found a similar signal.

Trait	PP.H4	lead_p	study_ID	Source
Personality traits or cognitive traits (multivariate analysis)	0.95	1.9e-11	GCST90270074	Open Targets
Effector Memory CD4+ T cell %CD4+ T cell	0.90	1.2e-05	ebi-a-GCST90001543	OpenGWAS
Spinal stenosis	0.87	3.4e-05	finn-b-M13_SPINSTENOSIS	OpenGWAS
Worry too long after embarrassment	0.87	9.5e-08	ukb-b-13653	OpenGWAS
Plays computer games	0.82	9.6e-06	ukb-b-4779	OpenGWAS
rfMRI connectivity (ICA100 edge 1173)	0.81	4.2e-06	ubm-b-3601	OpenGWAS
Miserableness	0.80	2.1e-07	ukb-a-46	OpenGWAS
aparc-a2009s_rh_thickness_S-central	0.78	7.2e-06	ubm-b-1296	OpenGWAS
aparc-a2009s_rh_volume_G+S-transv-frontopol	0.78	2.1e-05	ubm-b-578	OpenGWAS
Educational attainment (years of education)	0.77	2.9e-06	ebi-a-GCST90029013	OpenGWAS
Feeling miserable	0.77	9.2e-07	ebi-a-GCST006943	OpenGWAS
rfMRI connectivity (ICA25 edge 102)	0.74	3.5e-07	ubm-b-2320	OpenGWAS
rfMRI connectivity (ICA100 edge 583)	0.73	4.8e-05	ubm-b-3011	OpenGWAS
NET100 0687	0.72	1.2e-05	ubm-a-1843	OpenGWAS
Miserableness	0.71	5.1e-07	ukb-b-18994	OpenGWAS
Pappalysin-1 levels	0.71	6.0e-05	ebi-a-GCST90010155	OpenGWAS
Qualifications: College or University degree	0.70	1.4e-06	ukb-a-397	OpenGWAS
rfMRI connectivity (ICA100 edge 237)	0.67	2.8e-05	ubm-b-2665	OpenGWAS
Miserableness (UKB data field 1930) (Firth correction)	0.65	2.1e-06	ebi-a-GCST90013874	OpenGWAS
Miserableness (UKB data field 1930) (SPA correction)	0.65	2.1e-06	ebi-a-GCST90013924	OpenGWAS

 

[ME/CFS Science Blog]

Here's the gene card:

CACNA1E encodes the alpha-1E subunit of R-type voltage-gated calcium channels, a high-voltage-activated channel that mediates calcium influx in excitable cells. In neurons and neuroendocrine cells, these channels generate R-type calcium currents that regulate neuronal firing patterns, neurotransmitter release, and hormone secretion. The channel is part of the voltage-dependent calcium channel complex and is expressed at measurable levels in brain.

The channel localizes to the plasma membrane, membrane, cytosol, and actin cytoskeleton. Through depolarization-triggered calcium entry, CACNA1E participates in calcium-dependent processes including synaptic plasticity and cellular excitability. Alternative spliced transcript variants encoding different isoforms have been described, and the gene is linked to neuronal system and signaling pathways.

Pathogenic variants in CACNA1E are reported in developmental and epileptic encephalopathy 69, early infantile epileptic encephalopathy, and distal arthrogryposis. Clinical associations also include developmental and epileptic encephalopathy more broadly, with variants reported for van der Woude syndrome 1. Therapeutic context includes gabapentin, gabapentin enacarbil, pregabalin, atagabalin, bepridil hydrochloride, and imagabalin.

CACNA1E Gene - GeneCards

 

[SNT Gatchaman]

Molecular architecture of human dermal sleeping nociceptors (2026) —

We identified four Aδ groups: Aδ-LTMR, with uniquely high expression of PIEZO2 and marked by PCDH7, KCNQ3, and NTRK2; Aδ-CACNA1E, marked by B4GALT6, DCC, CREB5, CACNA1E, and— unique among Aδ-fibers— by its relatively high expression of SCN10A; Aδ-TRPV1, marked by UNC5D and ZNF521 and with distinctively high expression of the capsaicin and heat receptor TRPV1; and Aδ-COOL, marked by the cold- and menthol-sensitive ion channel TRPM8, RORA, and FOXP2 expression.

Listed in table A3: gene list for the tinnitus pathway in the auditory system Candidate Key Proteins of Tinnitus in the Auditory and Motor Systems of the Thalamus (2025) although not especially high up in that table.

Listed in Table 2 Over-representation analysis of the 716 genes showed nominal significance in both the family cohort and the case–control cohort in The genetic landscape of pediatric postural orthostatic tachycardia syndrome (2025)