A human phenome-interactome network of protein complexes implicated in genetic disorders

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Abstract

We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.

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Figure 1: Steps in scoring each candidate in a linkage interval.
Figure 2: Performance of the Bayesian predictor.
Figure 3: Case studies of four candidate complexes.

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Acknowledgements

The authors wish to thank Ulrik de Lichtenberg and Thomas Skøt Jensen for critical reading of the manuscript, editing and help in developing the protein interaction score. We also thank Christopher Workman and Zoltan Szallasi for valuable discussions and help with the manuscript. Y.M. is supported by K.U. Leuven GOA AMBioRICS, CoE EF/05/007 SymBioSys, BELSPO IUAP P6/25 BioMaGNet, EU-FP6-NoE Biopattern and EU-FP6-MC-EST Bioptrain. Z.M.S. is supported by an EU Biosapiens (NoE), FP6 grant. The Center for Biological Sequence Analysis and the Wilhelm Johannsen Center for Functional Genome Research are supported by the Danish National Research Foundation.

Author information

Correspondence to Søren Brunak.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Measuring phenotype association scores between OMIM records. (PDF 287 kb)

Supplementary Fig. 2

Benchmark of the phenotype association score. (PDF 81 kb)

Supplementary Fig. 3

Benchmark of protein interaction score. (PDF 115 kb)

Supplementary Fig. 4

EOC candidate complex. (PDF 153 kb)

Supplementary Fig. 5

IBD candidate complex. (PDF 290 kb)

Supplementary Fig. 6

ALS with frontotemporal dementia candidate complex. (PDF 219 kb)

Supplementary Fig. 7

Influence of tf-idf weight on phenotype similarity scoring scheme. (PDF 83 kb)

Supplementary Fig. 8

Robustness of the cosine phenotype similarity measure. (PDF 79 kb)

Supplementary Fig. 9

Connection profiles. (PDF 101 kb)

Supplementary Fig. 10

Performance of phenotype similarity scheme on phenotypes with same molecular basis. (PDF 107 kb)

Supplementary Table 1

A randomly selected subset of 100 OMIM record pairs crossreferenced by the OMIM curators. (PDF 35 kb)

Supplementary Table 2

A list of 113 candidates identified by the Bayesian predictor. (PDF 30 kb)

Supplementary Table 3

Comparison of the different computational methods that have been tested by ranking candidate genes in linkage intervals. (PDF 7 kb)

Supplementary Table 4

Normalized connectivity of phenotypes from the training set and the prediction set. (PDF 12 kb)

Supplementary Table 5

Benchmarking subset where we ranked the correct gene as number one out of all candidates in the interval. (PDF 46 kb)

Supplementary Data (PDF 23 kb)

Supplementary Methods (PDF 148 kb)

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