Genetics: locus 13: 58,456,743 - genes PCDH17

[ME/CFS Science Blog]

This was a signal just below the significance threshold (9.4 × 10⁻⁷) in DecodeME.

The top hit is 13:58456743:T:C. T is the common allele has a frequency of 98.8% in cases and 98.4% in controls. This means that the rare C allele (1.2% in cases, 1.6% in controls) is protective and associated with lower odds of ME/CFS.

The signal lies in a gene desert. SUSIE couldn't finemap a credible set so the plot highlights 10 SNPs that hold 34% of the probability. It lies in a non-coding RNA called ENSG00000302133. The two closest protein-coding genes are far off: PCDH17 on the west side and DIAPH3 on the east side. FLAMES didn't consider them because it's restricted to 750 kb.




The Hi-C domains suggest folding stretched out to the west side to PCDH17 so I think that is the most likely candidate gene.



The eQTL didn't find a good match but possibly because the (brain) datasets were too small (the lead_p is weak and that results in lower PP.H4). The PCDH17 signals in the brain suggest that the risk alleles raise PCDH17.

Trait (gene)	Study	PP.H4	lead_p	risk_allele
PCDH17	GTEx_v10 | testis | naive | QTD000336	0.17	1.5e-03	lowers (z = -2.8)
PCDH17	GTEx_v10 | brain (putamen) | naive | QTD000196	0.16	2.7e-04	raises (z = 3.7)
PCDH17	Jerber_2021 | dopaminergic neuron | rotenone_D52 | QTD000633	0.14	2.8e-03	lowers (z = -1.7)
ENSG00000278722 [ILMN_3195119]	Fairfax_2014 | monocyte | LPS_2h | QTD000083	0.13	1.1e-03	raises (z = 1.9)
ENSG00000288765	GTEx_v10 | kidney (cortex) | naive | QTD000261	0.13	7.1e-05	raises (z = 0.9)
PCDH17	GTEx_v10 | adipose | naive | QTD000116	0.13	3.5e-03	raises (z = 2.8)
PCDH17 [ILMN_1781514]	Kasela_2017 | CD4+ T cell | naive | QTD000371	0.12	2.3e-03	raises (z = 2.2)
ENSG00000278722 [ILMN_3195119]	Fairfax_2014 | monocyte | naive | QTD000081	0.11	9.7e-03	raises (z = 2.4)
ENSG00000278722 [ILMN_3195119]	Fairfax_2014 | monocyte | LPS_24h | QTD000084	0.10	1.8e-04	raises (z = 1.8)
ENSG00000278722 [ILMN_3271581]	CEDAR | neutrophil | naive | QTD000070	0.10	6.8e-03	raises (z = 0.1)
PCDH17	GTEx_v10 | brain (caudate) | naive | QTD000156	0.10	1.8e-02	raises (z = 2.2)

Lastly, here are the results from GWAS with a similar signal. The top hit is place of birth in the UK suggesting that selection bias might be an issue here (although DecodeME tried to account for this).

Trait	PP.H4	lead_p	study_ID	Source
Place of birth in UK - east co-ordinate	0.94	3.2e-11	ukb-b-13231	OpenGWAS
Nap during day	0.91	1.6e-07	ukb-b-4616	OpenGWAS
Peak expiratory flow (PEF)	0.91	8.8e-07	ukb-b-12019	OpenGWAS
Daytime nap	0.89	3.3e-07	ebi-a-GCST011494	OpenGWAS
Nap during day	0.88	2.1e-06	ukb-a-12	OpenGWAS
Coagulation factor IX measurement	0.88	3.6e-05	ebi-a-GCST90019451	OpenGWAS
Urinary sodium-potassium ratio	0.84	5.0e-06	ieu-b-72	OpenGWAS
Ever smoked	0.83	1.3e-07	ukb-a-236	OpenGWAS
Systolic blood pressure, automated and manual reading, restrict to 60-73 years	0.82	3.3e-05	ieu-b-5168	OpenGWAS
Peak expiratory flow (PEF)	0.82	2.2e-05	ukb-a-338	OpenGWAS
Standing height	0.81	7.8e-06	ukb-b-10787	OpenGWAS
rfMRI connectivity (ICA100 edge 1148)	0.79	5.3e-05	ubm-b-3576	OpenGWAS
Sodium in urine (UKB data field 30530)	0.79	2.3e-06	ebi-a-GCST90013989	OpenGWAS
Number of treatments/medications taken	0.71	1.6e-05	ukb-b-3656	OpenGWAS
Height	0.66	9.6e-08	ebi-a-GCST90029008	OpenGWAS
Taking other prescription medications	0.52	2.2e-05	ukb-b-20292	OpenGWAS
Ever smoked	0.48	4.3e-08	ukb-b-20261	OpenGWAS
Medication for pain relief, constipation, heartburn: None of the above	0.42	1.5e-06	ukb-b-11085	OpenGWAS
Frequency of tiredness / lethargy in last 2 weeks	0.40	2.1e-05	ukb-b-929	OpenGWAS
Number of unenthusiastic/disinterested episodes	0.31	8.0e-07	ukb-b-1998	OpenGWAS

 

[ME/CFS Science Blog]

Here's the gene card of PCDH17. Might be related to PCDH8 which came up in an earlier locus.

PCDH17 encodes protocadherin 17, a cell-adhesion protein that participates in specific cell-cell connections in the brain. It belongs to the protocadherin gene family within the cadherin superfamily and is associated with homophilic cell-cell adhesion. The protein has six extracellular cadherin domains, a transmembrane domain, and a cytoplasmic tail that differs from classical cadherins.

PCDH17 localizes to the plasma membrane, cytosol, intracellular membrane-bounded organelles, and the GABA-ergic synapse, placing it in compartments relevant to synaptic organization. Its biological process labels include negative regulation of synaptic transmission, regulation of synaptic vesicle clustering, and presynaptic active zone assembly, alongside synaptic membrane adhesion. Expression measurements show high protein levels in the endocrine system, respiratory system, and proximal digestive tract, with RNA expression also detected in the hematopoietic system and respiratory system.

Pathogenic variants in PCDH17 are reported in neurodevelopmental and neurologic disease contexts. PCDH17 has been linked to intellectual disability, epilepsy, and adult behavior phenotypes.

PCDH17 Gene - GeneCards

 

[ME/CFS Science Blog]

Place of birth in UK - east co-ordinate

This being the top hit means that participation is also a risk here.