Network models of genome-wide association studies uncover the topological centrality of protein interactions in complex diseases
- Younghee Lee1,2,
- Haiquan Li1,2,3,
- Jianrong Li1,2,3,
- Ellen Rebman1,3,
- Ikbel Achour3,
- Kelly E Regan3,4,
- Eric R Gamazon2,
- James L Chen1,4,
- Xinan Holly Yang1,2,
- Nancy J Cox2,5,
- Yves A Lussier1,2,3,5,6
- 1Center for Biomedical Informatics, The University of Chicago, Chicago, Illinois, USA
- 2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA
- 3Department of Medicine, The University of Illinois at Chicago, Chicago, Illinois, USA
- 4Departments of Biomedical Informatics and Internal Medicine (Division of Medical Oncology), Ohio State University College of Medicine, Columbus, Ohio, USA
- 5Institute for Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, USA
- 6Computation Institute, The University of Chicago, Chicago, Illinois, USA
- Correspondence to Dr Yves A Lussier, 909 South Wolcott Avenue, Chicago, IL 60612, USA;
- Received 5 December 2012
- Revised 5 December 2012
- Accepted 5 January 2013
- Published Online First 25 January 2013
Background While genome-wide association studies (GWAS) of complex traits have revealed thousands of reproducible genetic associations to date, these loci collectively confer very little of the heritability of their respective diseases and, in general, have contributed little to our understanding the underlying disease biology. Physical protein interactions have been utilized to increase our understanding of human Mendelian disease loci but have yet to be fully exploited for complex traits.
Methods We hypothesized that protein interaction modeling of GWAS findings could highlight important disease-associated loci and unveil the role of their network topology in the genetic architecture of diseases with complex inheritance.
Results Network modeling of proteins associated with the intragenic single nucleotide polymorphisms of the National Human Genome Research Institute catalog of complex trait GWAS revealed that complex trait associated loci are more likely to be hub and bottleneck genes in available, albeit incomplete, networks (OR=1.59, Fisher's exact test p<2.24×10−12). Network modeling also prioritized novel type 2 diabetes (T2D) genetic variations from the Finland–USA Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics and the Wellcome Trust GWAS data, and demonstrated the enrichment of hubs and bottlenecks in prioritized T2D GWAS genes. The potential biological relevance of the T2D hub and bottleneck genes was revealed by their increased number of first degree protein interactions with known T2D genes according to several independent sources (p<0.01, probability of being first interactors of known T2D genes).
Conclusion Virtually all common diseases are complex human traits, and thus the topological centrality in protein networks of complex trait genes has implications in genetics, personal genomics, and therapy.
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