Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology
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Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.
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DAPPLE analysis of the union set of 336 unique genes resulted in a network of direct PPIs encoded by 151 genes, with 54/92 (58.7%) ASD genes, 64/113 (56.6%) de novo CNV genes, and 41/122 (33.6%) de novo LoF SNV genes.
“The union set of 336 unique genes (Table S15) analyzed by DAPPLE37 resulted in a network of direct PPIs encoded by 151 genes (Figure 5A) from each of the three main lists: 54/92 (58.7%) genes involved in ASD, 64/113 (56.6%) de novo CNV genes, and 41/122 (33.6%) de novo LoF SNV genes.”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [37]
Network edges are susceptible to ascertainment biases and confounding factors that can induce spurious relationships.
“Notably, edges are susceptible to ascertainment biases52,214,215 and confounding factors that can induce spurious relationships178 (FIG. 2b).”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [214]
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- Authors
- Rossin, E. J., Lage, K., Raychaudhuri, S., Xavier, R. J., Tatar, D., Benita, Y., Constortium, I. I. B. D. G., Cotsapas, C., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Daly, Mark J.
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-13
- Volume
- 7
- Issue
- 1
- Pages
- e1001273
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3020935
- OpenAlex
- W2081038787
- Cited by
- 438
- References
- 68
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 12 · 2021: 11 · 2020: 18 · 2019: 28 · 2018: 38 · 2017: 33 · 2016: 49 · 2015: 60 · 2014: 54 · 2013: 58 · 2012: 44
- FWCI
- 22.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
- Research Explorer (The University of Manchester) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Figshare (submittedVersion, cc-by)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- Wellcome Trust
- National Institutes of Health (5r01hd055150-05, DK083756)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK083756, P01DK046763, DK083756, DK086502, RC1DK086502, R01DK064869, P30DK043351, P30DK040561)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD0551-50, R01 HD055150-03)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biomedical Text Mining and Ontologies
- Keywords
- protein-protein interaction network, immune-mediated diseases, rheumatoid arthritis, Crohn's disease, complex disease genetics, genetic susceptibility loci, network density, tissue expression, type 2 diabetes, height, serum lipids
- MeSH terms
- Arthritis, Rheumatoid, Crohn Disease, Diabetes Mellitus, Type 2, Humans, Genome, Gene Regulatory Networks, Genome-Wide Association Study, Genetic Loci
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