SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse
Open accessAbstract
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).
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Our Syn-GO gene-set enrichment analysis [38] identified that the pathways related to vesicle cycling or exocytosis were suppressed in 5xFAD mice.
“our Syn-GO gene-set enrichment analysis [38] identified that the pathways related to vesicle cycling or exocytosis were suppressed in 5xFAD mice.”
From Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease (2023) · cites this paper as [38]
SynGO analysis of downregulated DEGs in both MGE and CGE InNs confirmed significant enrichment (q-value < 0.01) for PSD membrane-associated components.
“SynGO (30) analysis of downregulated DEGs in both MGE and CGE InNs confirmed significant enrichment (q-value < 0.01) for PSD membrane-associated components (Fig. 4, C and D, fig. S11).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [30]
SynGO analysis identified Ts21-downregulated DEGs encoding proteins predominantly localized to the postsynaptic density (PSD) membrane, with functional roles enriched for synaptic organization.
“SynGO (30) analysis identified Ts21-downregulated DEGs encoding proteins predominantly localized to the postsynaptic density (PSD) membrane, with functional roles enriched for synaptic organization (Fig. 3F, fig. S9 and table S6).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [30]
Genes are downregulated in CGE InN and MGE InN, with synaptic cellular component ontology enrichment.
“( C and D ) SynGO (30) plot of genes downregulated in CGE InN (C) or MGE InN (D).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [30]
Genes downregulated in Ts21 L2-3 ExN are enriched for synaptic cellular component ontology terms.
“( F ) SynGO (30) plot of genes downregulated in Ts21 L2-3 ExN. Each bar represents a synaptic cellular component ontology term with concentric rings representing progressively more specific subclasses of synaptic terms.”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [30]
We found consistent enrichment for postsynaptic components and processes in the SynGO synaptic ontology (GO:0098794; P = 3.9 x 10 - 6 ).
“Because of the clear synaptic signal, we investigated in the refined synaptic ontology defined by the SynGO consortium 31 , and found consistent enrichment for postsynaptic components and processes (GO:0098794; P = 3.9 x 10 - 6 ; Table S7).”
From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [31]
Pathway analyses of common variants have prioritized disease-relevant tissues and cell types and sometimes recapitulated known biology.
“Pathway analyses of common variants have prioritized disease-relevant tissues and cell types, and in some cases, independently recapitulating known biology8,30,31.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [31]
Genes with highest specific expression in brain regions show strongest enrichment of risk URVs, most significantly in human frontal cortex (P=1.63e-8), with limited signal in other tissues.
“Following earlier reports studying heritability enrichment in GTEx tissues8,31, we found that genes with the highest specific expression in brain regions showed the strongest enrichment of risk URVs, most significantly in the human frontal cortex (P = 1.63 × 10−8) and with limited signal in the other tissue types (Extended Data Figure 4, Table S8, S9).”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [31]
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Self-citationSystems approach to explore components and interactions in the presynapse
Abul‐Husn, N. S., Bushlin, I., Morón, J. A., Jenkins, S. L., Dolios, G., Wang, R., Iyengar, R., Ma'ayan, A., & Devi, L. A. (2009) · PROTEOMICS · doi:10.1002/pmic.200800767 · Cited by 53 · see citing works
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Neurodegeneration: New Road Leads Back to the Synapse
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
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Cited by
Sorted by citations
The Gene Ontology resource: enriching a GOld mine
The Gene Ontology Consortium, Carbon, S., Douglass, E., Good, B. M., Unni, D. R., Harris, N. L., Mungall, C. J., Basu, S., Chisholm, R. L., Dodson, R. J., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa1113 · Cited by 3,555 · see citing works
Self-citationMapping genomic loci implicates genes and synaptic biology in schizophrenia
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964 · see citing works
Self-citationRare coding variants in ten genes confer substantial risk for schizophrenia
Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., et al. (2022) · Nature · doi:10.1038/s41586-022-04556-w · Cited by 983 · see citing works
Self-citationComparative cellular analysis of motor cortex in human, marmoset and mouse
Bakken, T. E., Jorstad, N. L., Hu, Q., Lake, B. B., Tian, W., Kalmbach, B. E., Crow, M., Hodge, R. D., Krienen, F. M., Sorensen, S. A., et al. (2021) · Nature · doi:10.1038/s41586-021-03465-8 · Cited by 812 · see citing works
Self-citationMathys, H., Peng, Z., Boix, C. A., Victor, M. B., Leary, N., Babu, S., Abdelhady, G., Jiang, X., Ng, A. P., Ghafari, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.039 · Cited by 495 · see citing works
Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease
Otero-Garcia, M., Mahajani, S. U., Wakhloo, D., Tang, W., Xue, Y.-Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A. E., Shakouri, T., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.021 · Cited by 262 · see citing works
Comparative transcriptomics reveals human-specific cortical features
Jorstad, N. L., Song, J. H. T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F. M., Yanny, A. M., Close, J., Gelfand, E., Long, B., et al. (2023) · Science · doi:10.1126/science.ade9516 · Cited by 208 · see citing works
“Byperforminggenesetenrich-mentanalysisusingSynGO( 28 ), we found a significant enrichment of hDEGs among SynGO genes compared with all expressed genes ( P 10 − 16 ) and a further enrichment of hDEGs near HARs and hCONDELs among SynGO genes compared with all hDEGs ( P 10 − 5 ) (Fig.”
BackgroundMethodInfluentialSingh, T., Neale, B. M., & Daly, M. J. (2020) · doi:10.1101/2020.09.18.20192815 · Cited by 980 · see citing works
Self-citationCaglayan, E., Liu, Y., & Konopka, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.09.010 · Cited by 123 · see citing works
The proteomic landscape of synaptic diversity across brain regions and cell types
van Oostrum, M., Blok, T. M., Giandomenico, S. L., tom Dieck, S., Tushev, G., Fürst, N., Langer, J. D., & Schuman, E. M. (2023) · Cell · doi:10.1016/j.cell.2023.09.028 · Cited by 135 · see citing works
Genetics of schizophrenia in the South African Xhosa
Gulsuner, S., Stein, D. J., Susser, E. S., Sibeko, G., Pretorius, A., Walsh, T., Majara, L., Mndini, M. M., Mqulwana, S. G., Ntola, O. A., et al. (2020) · Science · doi:10.1126/science.aay8833 · Cited by 118 · see citing works
An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury
Hilton, B. J., Husch, A., Schaffran, B., Lin, T.-C., Burnside, E. R., Dupraz, S., Schelski, M., Kim, J., Müller, J. A., Schoch, S., et al. (2022) · Neuron · doi:10.1016/j.neuron.2021.10.007 · Cited by 116 · see citing works
Self-citationEvolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse
Bakken, T. E., Jorstad, N. L., Hu, Q., Lake, B. B., Tian, W., Kalmbach, B. E., Crow, M., Hodge, R. D., Krienen, F. M., Sorensen, S. A., et al. (2020) · doi:10.1101/2020.03.31.016972 · Cited by 809 · see citing works
Self-citationDendritic Spines: Mediators of Cognitive Resilience in Aging and Alzheimer’s Disease
Walker, C. K., & Herskowitz, J. H. (2021) · The Neuroscientist · doi:10.1177/1073858420945964 · Cited by 86 · see citing works
A cross-species proteomic map reveals neoteny of human synapse development
Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., et al. (2023) · Nature · doi:10.1038/s41586-023-06542-2 · Cited by 82 · see citing works
A cross-species proteomic map reveals neoteny of human synapse development
Wang, L., Pang, K., Zhou, L., Cebrián-Silla, A., González-Granero, S., Wang, S., Bi, Q., White, M. L., Ho, B., Li, J., et al. (2022) · doi:10.1101/2022.10.24.513541 · Cited by 82 · see citing works
The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease
Bendl, J., Hauberg, M. E., Girdhar, K., Im, E., Vicari, J. M., Rahman, S., Fernando, M. B., Townsley, K. G., Dong, P., Misir, R., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01166-7 · Cited by 65 · see citing works
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
Eteleeb, A. M., Novotny, B. C., Tarraga, C. S., Sohn, C., Dhungel, E., Brase, L., Nallapu, A., Buss, J., Farias, F., Bergmann, K., et al. (2024) · PLOS Biology · doi:10.1371/journal.pbio.3002607 · Cited by 64 · see citing works
The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia
Nehme, R., Pietiläinen, O., Artomov, M., Tegtmeyer, M., Valakh, V., Lehtonen, L., Bell, C., Singh, T., Trehan, A., Sherwood, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31436-8 · Cited by 58 · see citing works
Self-citationThe needs of a synapse—How local organelles serve synaptic proteostasis
Grochowska, K. M., Andres‐Alonso, M., Karpova, A., & Kreutz, M. R. (2022) · The EMBO Journal · doi:10.15252/embj.2021110057 · Cited by 38 · see citing works
Self-citationCTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny
Assendorp, N., Fossati, M., Libé-Philippot, B., Christopoulou, E., Depp, M., Rapone, R., Dingli, F., Loew, D., Vanderhaeghen, P., & Charrier, C. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114797 · Cited by 32 · see citing works
Oh, H., Lee, S., Oh, Y., Kim, S., Kim, Y. S., Yang, Y., Choi, W., Yoo, Y.-E., Cho, H., Lee, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39203-z · Cited by 32 · see citing works
Self-citationJang, J., Yeo, S., Baek, S., Jung, H. J., Lee, M. S., Choi, S. H., & Choe, Y. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01637-3 · Cited by 20 · see citing works
“Also, our Syn-GO gene-set enrichment analysis [38] identified that the pathways related to vesicle cycling or exocytosis were suppressed in 5xFAD mice.”
BackgroundSelf-citationRare genetic variants confer a high risk of ADHD and implicate neuronal biology
Demontis, D., Duan, J., Hsu, Y.-H. H., Pintacuda, G., Grove, J., Nielsen, T. T., Thirstrup, J., Martorana, M., Botts, T., Satterstrom, F. K., et al. (2026) · Nature · doi:10.1038/s41586-025-09702-8 · Cited by 17 · see citing works
Self-citationSlota, J. A., Medina, S. J., Frost, K. L., & Booth, S. A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.918811 · Cited by 16 · see citing works
Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex
Risgaard, R. D., Hanthanan Arachchilage, K., Knaack, S. A., Hosseini, M., Chen, R. J., Kumarage, P., Schmidt, D. K., Huang, X., Sheng, J., Wang, C. J., et al. (2026) · Science · doi:10.1126/science.aea1549 · Cited by 12 · see citing works
Pulcrano, S., De Gregorio, R., De Sanctis, C., Volpicelli, F., Piscitelli, R. M., Speranza, L., Perrone-Capano, C., di Porzio, U., Caiazzo, M., Martini, A., et al. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.0431-23.2023 · Cited by 12 · see citing works
Milestone Review: Unlocking the Proteomics of Glycine Receptor Complexes
Fraser, S. D., Klaassen, R. V., Villmann, C., Smit, A. B., & Harvey, R. J. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70061 · Cited by 10 · see citing works
“…on synaptic PPIs is integrated into publicly available platforms such as SynGO (Synaptic Gene Ontology), an expert-curated universal reference for synapse research and an online analysis platform for interpretation of large-scale proteomics data (Koopmans et al. 2019; https:// syngo portal. org).”
Self-citationFluid markers of synapse degeneration in synucleinopathies
Cervantes González, A., & Belbin, O. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-022-02467-8 · Cited by 7 · see citing works
MicroRNA‐138‐5p suppresses excitatory synaptic strength at the cerebellar input layer
Delvendahl, I., Daswani, R., Winterer, J., Germain, P., Uhr, N. M., Schratt, G., & Müller, M. (2025) · The Journal of Physiology · doi:10.1113/jp288019 · Cited by 3 · see citing works
- Authors
- Koopmans, F., van Nierop, P., Andres-Alonso, M., Byrnes, A., Cijsouw, T., Coba, M. P., Cornelisse, L. N., Farrell, R. J., Goldschmidt, H. L., Howrigan, D. P., Hussain, N. K., Imig, C., de Jong, A. P. H., Jung, H., Kohansalnodehi, M., Kramarz, B., Lipstein, N., Lovering, R. C., MacGillavry, H., Mariano, V., Mi, H., Ninov, M., Osumi-Sutherland, D., Pielot, R., Smalla, K.-H., Tang, H., Tashman, K., Toonen, R. F. G., Verpelli, C., Reig-Viader, R., Watanabe, K., van Weering, J., Achsel, T., Ashrafi, G., Asi, N., Brown, T. C., De Camilli, P., Feuermann, M., Foulger, R. E., Gaudet, P., Joglekar, A., Kanellopoulos, A., Malenka, R., Nicoll, R. A., Pulido, C., de Juan-Sanz, J., Sheng, M., Südhof, T. C., Tilgner, H. U., Bagni, C., Bayés, À., Biederer, T., Brose, N., Chua, J. J. E., Dieterich, D. C., Gundelfinger, E. D., Hoogenraad, C., Huganir, R. L., Jahn, R., Kaeser, P. S., Kim, E., Kreutz, M. R., McPherson, P. S., Neale, B. M., O’Connor, V., Posthuma, D., Ryan, T. A., Sala, C., Feng, G., Hyman, S. E., Thomas, P. D., Smit, A. B., & Verhage, M.
- Affiliations
- Vrije Universiteit Amsterdam (NL)
- Broad Institute (US)
- Tufts University (US)
- University of Southern California (US)
- Weill Cornell Medicine (US)
- Johns Hopkins University (US)
- Max Planck Institute of Experimental Medicine (DE)
- Korea Advanced Institute of Science and Technology (KR)
- University College London (GB)
- Utrecht University (NL)
- University of Rome Tor Vergata (IT)
- Max Planck Institute for Biophysical Chemistry (DE)
- European Bioinformatics Institute (GB)
- Center for Behavioral Brain Sciences (DE)
- University of Milan (IT)
- Amsterdam Neuroscience (NL)
- SIB Swiss Institute of Bioinformatics (CH)
- Stanford University (US)
- University of California, San Francisco (US)
- Genentech (US)
- Howard Hughes Medical Institute (US)
- Universitat Autònoma de Barcelona (ES)
- National University of Singapore (SG)
- Harvard University (US)
- Universität Hamburg (DE)
- Montreal Neurological Institute and Hospital (CA)
- Corresponding author
- Smit, August B.
- Verhage, Matthijs
- ORCID
- Koopmans, Frank
- Cijsouw, Tony
- Coba, Marcelo P.
- Cornelisse, L. Niels
- Farrell, Ryan J.
- Goldschmidt, Hana L.
- Howrigan, Daniel P.
- Hussain, Natasha K.
- Imig, Cordelia
- Jung, Hwajin
- Kramarz, Barbara
- Lipstein, Noa
- Lovering, Ruth C.
- MacGillavry, Harold
- Mariano, Vittoria
- Mi, Huaiyu
- Ninov, Momchil
- Osumi-Sutherland, David
- Pielot, Rainer
- Smalla, Karl-Heinz
- Tang, Haiming
- Tashman, Katherine
- Toonen, Ruud F.G.
- Verpelli, Chiara
- Watanabe, Kyoko
- Achsel, Tilmann
- Ashrafi, Ghazaleh
- Brown, Tyler C.
- Feuermann, Marc
- Foulger, Rebecca E.
- Gaudet, Pascale
- Joglekar, Anoushka
- Kanellopoulos, Alexandros
- Malenka, Robert
- Nicoll, Roger A.
- Pulido, Camila
- Sheng, Morgan
- Südhof, Thomas C.
- Tilgner, Hagen U.
- Bagni, Claudia
- Bayés, Àlex
- Biederer, Thomas
- Brose, Nils
- Chua, John Jia En
- Dieterich, Daniela C.
- Gundelfinger, Eckart D.
- Hoogenraad, Casper
- Huganir, Richard L.
- Jahn, Reinhard
- Kaeser, Pascal S.
- Kim, Eunjoon
- Kreutz, Michael R.
- McPherson, Peter S.
- Ryan, Timothy A.
- Sala, Carlo
- Feng, Guoping
- Hyman, Steven E.
- Thomas, Paul D.
- Smit, August B.
- Verhage, Matthijs
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 103
- Issue
- 2
- Pages
- 217-234.e4
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6764089
- OpenAlex
- W2948949781
- Cited by
- 938
- References
- 84
- Citations by year
- 2026: 143 · 2025: 185 · 2024: 193 · 2023: 152 · 2022: 128 · 2021: 77 · 2020: 49 · 2019: 8 · 2012: 1
- FWCI
- 21.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- IRIS (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- The Stanley Center for Psychiatric Research
- The Broad Institute of MIT and Harvard
- European Union (SynPrime, ERC-ADG-322966-DCVfusion)
- EUROSPIN (HEALTH-F2-2009-241498)
- SYNSYS (HEALTH-F4-2010-242167, BFU2012-34398, BFU2015-69717-P)
- FEDER
- Ramón y Cajal (RYC-2011-08391)
- European FP People Marie Curie Action (304111)
- CERCA Program/Generalitat de Catalunya
- DFG (CRC779 Project B08, CRC779 Project B09)
- EU-JPND (STAD)
- Leibniz Foundation (SAW)
- NIH (NS36251)
- German Federal Ministry of Education and Research (ERA-NET Neuron Synpathy)
- ERC
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biomedical Text Mining and Ontologies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- synapses, synaptic genes, gene ontology annotation, knowledge base, synaptic processes, synaptopathy, genetic conservation, mutation tolerance, de novo mutations, neurodevelopmental disorders, schizophrenia, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, intelligence, educational attainment
- MeSH terms
- Animals, Brain, Humans, Software, Synapses, Synaptosomes, Databases, Genetic, Proteomics, Knowledge Bases, Synaptic Potentials, Gene Ontology
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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