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Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Elizabeth J Rossin, Kasper Lage, Soumya Raychaudhuri, Ramnik J Xavier, Diana Tatar, Yair Benita, Chris Cotsapas, Mark J Daly, the International Inflammatory Bowel Disease Genetics Constortium, Martine De Vos UGent, et al. (2011) PLOS GENETICS. 7(1).
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
SUSCEPTIBILITY LOCI, LARGE-SCALE REPLICATION, WIDE ASSOCIATION, RHEUMATOID-ARTHRITIS, CROHNS-DISEASE, CELIAC-DISEASE, INTERACTION NETWORK, GENETIC-VARIANTS, MOLECULAR INTERACTION DATABASE, INFLAMMATORY-BOWEL-DISEASE
journal title
PLOS GENETICS
PLoS Genet.
volume
7
issue
1
article number
e1001273
pages
13 pages
Web of Science type
Article
Web of Science id
000286653500012
JCR category
GENETICS & HEREDITY
JCR impact factor
8.694 (2011)
JCR rank
11/155 (2011)
JCR quartile
1 (2011)
ISSN
1553-7390
DOI
10.1371/journal.pgen.1001273
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1147045
handle
http://hdl.handle.net/1854/LU-1147045
date created
2011-02-11 11:36:44
date last changed
2016-12-21 15:42:34
@article{1147045,
  abstract     = {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.},
  articleno    = {e1001273},
  author       = {Rossin, Elizabeth J and Lage, Kasper and Raychaudhuri, Soumya and Xavier, Ramnik J and Tatar, Diana and Benita, Yair and Cotsapas, Chris and Daly, Mark J and International Inflammatory Bowel Disease Genetics Constortium, the and De Vos, Martine and Laukens, Debby},
  issn         = {1553-7390},
  journal      = {PLOS GENETICS},
  keyword      = {SUSCEPTIBILITY LOCI,LARGE-SCALE REPLICATION,WIDE ASSOCIATION,RHEUMATOID-ARTHRITIS,CROHNS-DISEASE,CELIAC-DISEASE,INTERACTION NETWORK,GENETIC-VARIANTS,MOLECULAR INTERACTION DATABASE,INFLAMMATORY-BOWEL-DISEASE},
  language     = {eng},
  number       = {1},
  pages        = {13},
  title        = {Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1001273},
  volume       = {7},
  year         = {2011},
}

Chicago
Rossin, Elizabeth J, Kasper Lage, Soumya Raychaudhuri, Ramnik J Xavier, Diana Tatar, Yair Benita, Chris Cotsapas, et al. 2011. “Proteins Encoded in Genomic Regions Associated with Immune-mediated Disease Physically Interact and Suggest Underlying Biology.” Plos Genetics 7 (1).
APA
Rossin, E. J., Lage, K., Raychaudhuri, S., Xavier, R. J., Tatar, D., Benita, Y., Cotsapas, C., et al. (2011). Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLOS GENETICS, 7(1).
Vancouver
1.
Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLOS GENETICS. 2011;7(1).
MLA
Rossin, Elizabeth J, Kasper Lage, Soumya Raychaudhuri, et al. “Proteins Encoded in Genomic Regions Associated with Immune-mediated Disease Physically Interact and Suggest Underlying Biology.” PLOS GENETICS 7.1 (2011): n. pag. Print.