Genetics: locus 2: 197,882,813 - genes PLCL1

[ME/CFS Science Blog]

Another locus that was just below the significance threshold (p = 6.6 × 10⁻⁷) in DecodeME. The A risk allele of the top hit was present in 50.9% of chromosomes in cases, 49.4% in controls, resulting in an odds ratio 1.065.

The credible set consisted of 249 SNPs (which is a lot) but the vast majority lie in the gene PLCL1, which is the most likely candidate. FLAMES also picks PLCL1 but wasn't confident enough to call it causal.



BOLL is also close by but the 3-D folding domain maps point to a region that stretches in the other direction to the east.



There's also some eQTL support for PLCL1 in various tissues such as immune cells. In most cases the ME/CFS risk allele raises the protein.

Trait (gene)	Study	PP.H4	lead_p	risk_allele
PLCL1 [ILMN_1718852]	Fairfax_2014 | monocyte | LPS_2h | QTD000083	0.88	4.7e-20	raises (z = 9.1)
PLCL1	OneK1K_reannotated | non-classical monocyte | naive | QTD000888	0.88	3.2e-17	raises (z = 8.5)
MARS2 [ILMN_1679177]	CEDAR | CD4+ T cell | naive | QTD000067	0.88	5.7e-13	lowers (z = -7.1)
PLCL1 [ILMN_1718852]	Kim-Hellmuth_2017 | monocyte | naive | QTD000752	0.87	1.7e-07	raises (z = 5.3)
RFTN2	GTEx_v10 | spleen | naive | QTD000326	0.87	2.1e-08	raises (z = 4.9)
PLCL1 [ILMN_1718852]	Kim-Hellmuth_2017 | monocyte | LPS_90min | QTD000756	0.86	8.5e-08	raises (z = 5.6)
RFTN2	GTEx_v10 | breast | naive | QTD000211	0.86	2.3e-08	raises (z = 5.6)
ENSG00000222017	OneK1K_reannotated | regulatory T cell | naive | QTD000889	0.85	2.8e-07	lowers (z = -4.7)
PLCL1	Randolph_2021_reannotated | NK cell | naive | QTD000842	0.85	5.3e-09	raises (z = 6.0)
PLCL1	BLUEPRINT | neutrophil | naive | QTD000026	0.84	1.1e-28	raises (z = 13.0)
PLCL1 [ILMN_1718852]	Kim-Hellmuth_2017 | monocyte | IVT_90min | QTD000754	0.84	2.7e-07	raises (z = 5.4)
PLCL1	Nathan_2022_reannotated | CD4+ TCM cell | naive | QTD000898	0.84	6.4e-09	raises (z = 5.9)
PLCL1	Schmiedel_2018 | CD16+ monocyte | naive | QTD000499	0.83	2.6e-09	raises (z = 6.5)
ENSG00000287858	Jerber_2021 | floor plate progenitor | naive_D11 | QTD000637	0.82	1.5e-06	lowers (z = -4.3)
ENSG00000222017	Nathan_2022_reannotated | regulatory T cell | naive | QTD000897	0.82	1.7e-06	lowers (z = -4.5)
PLCL1	Jerber_2021 | dopaminergic neuron | rotenone_D52 | QTD000633	0.81	4.5e-07	raises (z = 4.4)
PLCL1	Schmiedel_2018 | monocyte | naive | QTD000504	0.80	3.0e-11	raises (z = 7.5)
MARS2	GTEx_v10 | skin | naive | QTD000316	0.80	5.8e-07	lowers (z = -4.3)

The phewas also found a lot of other studies with a similar signal. I find it hard to find a matter in this or make sense out of it.

 

[mariovitali]

From what I see , PLCL1 is quite interesting @ME/CFS Science Blog

PLCL1 encodes a phospholipase C-related catalytically inactive protein that functions as a regulatory scaffold in phospho-dependent signaling. It is best known for its role in GABA A receptor endocytosis, where it helps maintain synaptic inhibition by regulating receptor turnover. PLCL1 also acts as an inhibitor of PPP1C, placing it at the intersection of receptor trafficking and phosphatase-regulated signaling.

PLCL1 is localized in the cytoplasm, consistent with its role in intracellular signaling control. It is linked to phosphatidylinositol-mediated signaling and the gamma-aminobutyric acid signaling pathway, and is predicted to bind GABA receptors. Tissue measurements show higher expression in the endocrine system, proximal digestive tract, and gastrointestinal tract, with detectable expression in brain.

Pathogenic variants in PLCL1 are not highlighted here, but altered expression or function could be relevant to signaling states that depend on receptor turnover and phosphatase regulation. In clinical contexts, PLCL1 has been associated with negative regulation of cold-induced thermogenesis and with signaling processes in the brain and gastrointestinal system.

Link : https://www.genecards.org/card/PLCL1

I also believe that PhosphatidylInositol signaling is of interest. Will write more about this

 

[mariovitali]

Alcohol intolerance and PLCL1 :

https://pubmed.ncbi.nlm.nih.gov/23743675/

@jnmaciuch could you have a look please at the involvement of calcium and PLCL1 (aka PRIP1) ?

https://pubmed.ncbi.nlm.nih.gov/15468068/

 

[jnmaciuch]

@jnmaciuch could you have a look please at the involvement of calcium and PLCL1 (aka PRIP1) ?

Sorry I don’t have much free time (or leftover cognitive capacity) lately. Did you have a specific question?

 

[mariovitali]

Sorry I don’t have much free time (or leftover cognitive capacity) lately. Did you have a specific question?

I quoted you because if my memory serves me well, you are interested in calcium metabolism. As I do not have the medical background, I do not understand whether there is an association of interest between PLCL1 and calcium release in neurons.

Sorry if this is not the case.

 

[SNT Gatchaman]

Gene Expression Correlates of Postinfective Fatigue Syndrome after Infectious Mononucleosis (2007)

PLCL1 stayed elevated across all time points in the Dubbo post-EBV PIFS transcriptomics study, in those sick throughout. High and falling in those sick then recovered. Lower in those well throughout.

 

[SNT Gatchaman]

See also Dissecting the genetic relationship between severe mental disorders and autoimmune diseases (2026) —

Another locus also linked to lipid metabolism, located on chromosome 2q33.1 (top lead SNP rs976180), was significant in six conjFDR analyses. Previously known to be associated with MD and BD (O’Connell et al., 2025; Adams et al., 2025), this locus implicates the Phospholipase C Like 1 (PLCL1) gene. Underscoring its importance, PLCL1 was also significant in three separate conditions in MAGMA (BD, SCZ, and RA), and has previously been linked to both RA and the development of SCZ. The PLCL1 protein works as a binding partner for protein phosphatase 1 and 2A, which play important roles in adipose tissue lipolysis, as well as other cellular functions, including glycogen metabolism and regulation of interferon production.

And, in spaaaaace...

Transcriptomics analysis reveals potential mechanisms underlying mitochondrial dysfunction and T cell exhaustion in astronauts’ blood cells in space (2025) —

Our data also shows the upregulation of ITPRIPL1, PLCL1, PLCD1 genes, indicating modulated IP3 activity.

Also mentioned in fig 5d in Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight (2024)