A tissue-specific atlas of protein–protein associations enables prioritization of candidate disease genes
Despite progress in mapping protein-protein interactions, their tissue specificity is understudied. Here, given that protein coabundance is predictive of functional association, we compiled and analyzed protein abundance data of 7,811 proteomic samples from 11 human tissues to produce an atlas of tissue-specific protein associations. We find that this method recapitulates known protein complexes and the larger structural organization of the cell. Interactions of stable protein complexes are well preserved across tissues, while cell-type-specific cellular structures, such as synaptic components, are found to represent a substantial driver of differences between tissues. Over 25% of associations are tissue specific, of which <7% are because of differences in gene expression. We validate protein associations for the brain through cofractionation experiments in synaptosomes, curation of brain-derived pulldown data and AlphaFold2 modeling. We also construct a network of brain interactions for schizophrenia-related genes, indicating that our approach can functionally prioritize candidate disease genes in loci linked to brain disorders.
Authors
- Matthias Gstaiger (ORCID: https://orcid.org/0000-0002-3245-3253)
- Kalpana Panneerselvam (ORCID: https://orcid.org/0000-0003-2534-198X)
- Andrea Fossati (ORCID: https://orcid.org/0000-0001-5170-4903)
- Delora Baptista (ORCID: https://orcid.org/0000-0002-9258-5303)
- Danish Memon (ORCID: https://orcid.org/0000-0002-1365-0710)
- Sandra Orchard (ORCID: https://orcid.org/0000-0002-8878-3972)
- Diederik S. Laman Trip
- Marc van Oostrum (ORCID: https://orcid.org/0000-0001-8747-9787)
- Luana Licata (ORCID: https://orcid.org/0000-0001-5084-9000)
- Pedro Beltrão (ORCID: https://orcid.org/0000-0002-2724-7703)
- Fabian Frommelt (ORCID: https://orcid.org/0000-0003-3666-8005)
- Ruedi Aebersold (ORCID: https://orcid.org/0000-0002-9576-3267)
- Ellen M. McDonagh (ORCID: https://orcid.org/0000-0001-5806-6174)
- Henning Hermjakob (ORCID: https://orcid.org/0000-0001-8479-0262)
- Bernd Wollscheid (ORCID: https://orcid.org/0000-0002-3923-1610)
- Gosia Trynka (ORCID: https://orcid.org/0000-0002-6955-9529)
- Glyn Bradley
Institutions
- University of Rome Tor Vergata (IT)
- SIB Swiss Institute of Bioinformatics (CH)
- European Bioinformatics Institute (GB)
- University of Basel (CH)
- Age UK (GB)
- Science for Life Laboratory (SE)
- Wellcome Sanger Institute (GB)
- Karolinska Institutet (SE)
- ETH Zurich (CH)
- Open Targets (GB)
- Bioinformatics Institute (RU)
- Instituto Gulbenkian de Ciência (PT)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1038/s41587-025-02659-z
- Citations
- 15
- Primary Topic
- Bioinformatics and Genomic Networks
- Type
- article
- Field-Weighted Citation Impact
- 12.09
Funders
- European Bioinformatics Institute