SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse, 2019, Koopmans et al.

[ME/CFS Science Blog]

Abstract​

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org).

Keywords: Gene Ontology; enrichment study; gene annotation; gene set analysis; synapse; synaptic plasticity; synaptic proteome network; synaptome; synaptopathies.

Link to the paper: https://www.cell.com/neuron/fulltext/S0896-6273(19)30427-1

 

[ME/CFS Science Blog]

The authors have created SynGO: several collections of genes involved in synaptic locations or processes. They made 303 of these expert-curated categories based on 1,112 synaptic genes.

The paper has some interesting info about these genes: that they tend to be longer than average and are highly conserved (“450 mya about 95% of all SynGO genes were already in place”) and highly intolerant to loss-of-function mutations.

The most interesting thing, however, is that we can test if genes associated with ME/CFS are enriched in these synaptic categories. We previously tested lots of these genes categories using the FUMA file: “MSigDB v2023.1Hs gene-set file” and some of the strongest signals pointed to synapses. Although there is some overlap, I think this SynGO database has many additional categories. So, it might help us pinpoint where the problem might lie in the synapses.

Here’s what I got using DecodeME:

Ontology_name	NGENES	P	P_bon
synapse adhesion between pre- and post-synapse (GO:0099560)	42	9.21E-07	2.38E-04
regulation of postsynaptic density assembly (GO:0099151)	22	3.12E-05	0.00805037
postsynaptic density membrane (GO:0098839)	140	3.14E-05	0.00810197
trans-synaptic signaling (GO:0099537)	207	4.99E-05	0.01286775
synaptic signaling (GO:0099536)	215	8.68E-05	0.02240137
postsynaptic process involved in chemical synaptic transmission (GO:0099565)	39	1.19E-04	0.03081036
postsynaptic modulation of chemical synaptic transmission (GO:0099170)	33	1.58E-04	0.04076658
presynapse assembly (GO:0099054)	14	1.65E-04	0.04254678
postsynaptic specialization (GO:0099572)	400	1.65E-04	0.04258032
postsynapse (GO:0098794)	1013	1.71E-04	0.04412832

I think these mostly point to the postsynaptic assembly and scaffolding, so more about how synapses get built and wired rather than how they fire and release neurotransmitters. Suspect others might give more insights into this.

 

[ME/CFS Science Blog]

Methods
I’ve downloaded the data version 1.3 here:
https://syngoportal.org/download

It includes 3 excel files. The ontologies.xlsx file has the name of the categories and the genes in it. To work with MAGMA, I created a file that has the name for each ontology, then all the gene ensemble IDs on one row separated by a whitespace.

Next the analysis is pretty much the same as with the cell type categories. I also tested the meta-analysis of DecodeME + MVP and a different window size for assigning SNPs to genes (0,0 and 35,10) but these had rather similar results.

ontology_name	NGENES	Pbon_decodeme_w0	P_decodeme_w0	P_decodeme_w35_10	P_meta_w0	P_meta_w35_10
synapse adhesion between pre- and post-synapse (GO:0099560)	42	2.38E-04	9.21E-07	7.39E-05	2.54E-05	3.18E-04
regulation of postsynaptic density assembly (GO:0099151)	22	0.00805037	3.12E-05	0.0058267	6.97E-04	0.0049157
postsynaptic density membrane (GO:0098839)	140	0.00810197	3.14E-05	1.20E-04	8.56E-06	2.45E-05
trans-synaptic signaling (GO:0099537)	207	0.01286775	4.99E-05	0.0011382	2.09E-05	2.60E-05
synaptic signaling (GO:0099536)	215	0.02240137	8.68E-05	0.001657	5.80E-05	5.20E-05
postsynaptic process involved in chemical synaptic transmission (GO:0099565)	39	0.03081036	1.19E-04	9.73E-05	1.81E-04	6.50E-05
postsynaptic modulation of chemical synaptic transmission (GO:0099170)	33	0.04076658	1.58E-04	1.03E-04	1.24E-04	1.32E-04
presynapse assembly (GO:0099054)	14	0.04254678	1.65E-04	5.44E-05	0.0082148	0.076585
postsynaptic specialization (GO:0099572)	400	0.04258032	1.65E-04	0.0010295	4.52E-05	3.78E-05
postsynapse (GO:0098794)	1013	0.04412832	1.71E-04	0.0027522	4.02E-04	1.29E-05

 

[forestglip]

Nice work! Makes sense to use MAGMA to zoom in on which component it could be.

I previously tried using the gene set analysis tool on SynGO's website to just look at how much overlap there is of the FLAMES genes with the synapse terms. It wasn't as detailed though, because there wasn't enough overlap between those genes and SynGO.

I just tried again to see what it shows. I used the list of genes from the FLAMES thread. And for background gene list, I used the 19274 protein-coding genes from HGNC. (Not sure if the possible genes that FLAMES outputs are limited to protein-coding genes or not. If not, the background list might need to include all possible genes.)

Cellular Component ontology terms

Ontology term	Gene count	p-value	adj. p-value
synapse	12	3.556e-6	1.422e-5
integral component of postsynaptic density membrane	3	0.0008624	0.001485
postsynapse	7	0.001114	0.001485
presynapse	6	0.001718	0.001718

Biological Process ontology terms

Ontology term	Gene count	p-value	adj. p-value
synaptic vesicle exocytosis	3	0.0003179	0.0006358
process in the synapse	7	0.003111	0.003111

The genes from ME/CFS FLAMES that are found in each of those gene sets:

synapse
KIAA1239 (NWD2)
UNC13C
ARFGEF2
HTT
RIMS1
PEBP1
CACNA1E
LAMA2
ALK
DCC
LRRC7
SHISA6

integral component of postsynaptic density membrane
DCC
LRRC7
SHISA6

postsynapse
ARFGEF2
ALK
HTT
DCC
LRRC7
SHISA6
CACNA1E

presynapse
UNC13C
ARFGEF2
HTT
RIMS1
PEBP1
CACNA1E

synaptic vesicle exocytosis
UNC13C
RIMS1
CACNA1E

process in the synapse
CACNA1E
UNC13C
RIMS1
SHISA6
HTT
ALK
DCC

So it seems pretty vague in terms of specific functions, but does still highlight how many of the 31 predicted FLAMES genes are involved in the synapse (at least 12).

 

[ME/CFS Science Blog]

We can also have a look at the genes inside the categories and the p-values MAGMA assigned them based on their association with ME/CFS. For the top category "synapse adhesion between pre- and post-synapse (GO:0099560)" the top genes were NRXN1 (neurexin-1) and NLGN1 (neuroligin-1) as well as PCDH17 which we previously linked to the striatum.



I then also took all the 1789 genes (in version 1 there were only 1112 genes but this has increased in version 3) that appear in SynGO as being related to synapses and ranked them based on their MAGMA p-value for their association with ME/CFS. Here are the top of these genes and the gene categories (ontology terms) they belong to.

hgnc_symbol	P	ontology_terms
LRRC7	4.16E-10	integral component of postsynaptic density membrane (GO:0099061)
STAU1	5.29E-09	modification of postsynaptic structure (GO:0099010); modulation of chemical synaptic transmission (GO:0050804); dendritic transport of messenger ribonucleoprotein complex (GO:0098963)
ARFGEF2	3.47E-07	postsynapse (GO:0098794); presynapse (GO:0098793)
CACNA1E	2.98E-06	integral component of presynaptic membrane (GO:0099056); integral component of postsynaptic membrane (GO:0099055); voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels (GO:0099626); regulation of synaptic vesicle exocytosis (GO:2000300)
DCC	4.58E-06	integral component of postsynaptic density membrane (GO:0099061); postsynaptic modulation of chemical synaptic transmission (GO:0099170)
PEBP1	4.88E-06	presynaptic membrane (GO:0042734)
VWC2	7.17E-06	extrinsic component of postsynaptic membrane (GO:0098890); neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645)
NEURL1	1.89E-05	postsynaptic density (GO:0014069); regulation of postsynapse assembly (GO:0150052)
INA	2.00E-05	postsynaptic intermediate filament cytoskeleton (GO:0099160); structural constituent of postsynaptic intermediate filament cytoskeleton (GO:0099184); postsynapse (GO:0098794); postsynaptic density, intracellular component (GO:0099092); postsynaptic modulation of chemical synaptic transmission (GO:0099170)
SHISA6	2.31E-05	integral component of postsynaptic density membrane (GO:0099061); postsynaptic neurotransmitter receptor diffusion trapping (GO:0098970); regulation of postsynaptic neurotransmitter receptor activity (GO:0098962)
DENND1A	3.66E-05	anchored component of synaptic vesicle membrane (GO:0098993); synaptic vesicle endocytosis (GO:0048488)
NRXN1	6.71E-05	integral component of presynaptic membrane (GO:0099056); regulation of trans-synaptic signaling by endocannabinoid, modulating synaptic transmission (GO:0150036); regulation of synaptic vesicle cycle (GO:0098693); presynapse assembly (GO:0099054); regulation of postsynaptic density assembly (GO:0099151); synapse adhesion between pre- and post-synapse (GO:0099560); regulation of presynapse assembly (GO:1905606); integral component of presynaptic active zone membrane (GO:0099059); regulation of postsynaptic specialization assembly (GO:0099150); synapse assembly (GO:0007416); trans-synaptic signaling, modulating synaptic transmission (GO:0099550)
SORCS3	6.85E-05	integral component of postsynaptic density membrane (GO:0099061); postsynaptic modulation of chemical synaptic transmission (GO:0099170)
PCDH17	7.75E-05	integral component of presynaptic membrane (GO:0099056); integral component of postsynaptic membrane (GO:0099055); synapse adhesion between pre- and post-synapse (GO:0099560)
SYT12	8.02E-05	integral component of synaptic vesicle membrane (GO:0030285); presynaptic modulation of chemical synaptic transmission (GO:0099171)
SPTBN2	1.02E-04	presynapse (GO:0098793); postsynaptic spectrin-associated cytoskeleton (GO:0099189); postsynapse organization (GO:0099173); structural constituent of postsynapse (GO:0099186); regulation of postsynaptic specialization assembly (GO:0099150)
MOB4	1.16E-04	postsynapse (GO:0098794)
RHOA	1.72E-04	regulation of modification of postsynaptic actin cytoskeleton (GO:1905274); postsynapse (GO:0098794); regulation of modification of postsynaptic structure (GO:0099159)
DNAJB1	1.79E-04	postsynaptic density (GO:0014069); postsynapse (GO:0098794)
EPHB1	1.87E-04	modulation of chemical synaptic transmission (GO:0050804)
TBC1D24	1.87E-04	synapse (GO:0045202); synaptic vesicle endosomal processing (GO:0099532); presynaptic endocytic zone membrane (GO:0098835)
CLCN3	2.44E-04	integral component of synaptic vesicle membrane (GO:0030285); synaptic vesicle proton loading (GO:0097401); integral component of postsynaptic membrane (GO:0099055)
NLGN1	2.65E-04	integral component of postsynaptic specialization membrane (GO:0099060); synapse adhesion between pre- and post-synapse (GO:0099560); regulation of presynapse organization (GO:0099174); postsynaptic specialization assembly (GO:0098698); regulation of postsynaptic density assembly (GO:0099151)
KCNB1	3.23E-04	integral component of postsynaptic specialization membrane (GO:0099060)
RTN4	3.81E-04	integral component of postsynaptic density membrane (GO:0099061); postsynapse (GO:0098794); modulation of chemical synaptic transmission (GO:0050804); regulation of postsynapse assembly (GO:0150052)
RPS10	4.37E-04	synapse (GO:0045202); postsynaptic ribosome; translation at presynapse (GO:0140236); presynaptic ribosome; translation at postsynapse (GO:0140242)
LRFN4	5.46E-04	integral component of postsynaptic density membrane (GO:0099061); regulation of presynapse assembly (GO:1905606); regulation of postsynaptic density assembly (GO:0099151); synapse adhesion between pre- and post-synapse (GO:0099560)
DAG1	6.18E-04	regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696); regulation of synapse organization (GO:0050807); retrograde trans-synaptic signaling by trans-synaptic protein complex (GO:0098942); postsynaptic cytosol (GO:0099524)
GRIA1	8.56E-04	integral component of presynaptic membrane (GO:0099056); integral component of postsynaptic membrane (GO:0099055); integral component of presynaptic active zone membrane (GO:0099059); integral component of postsynaptic density membrane (GO:0099061); ligand-gated ion channel activity involved in regulation of presynaptic membrane potential (GO:0099507); transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315)