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Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases

Nature Methods volume 13, pages 366–370 (2016)Cite this article

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Abstract

Mapping perturbed molecular circuits that underlie complex diseases remains a great challenge. We developed a comprehensive resource of 394 cell type– and tissue-specific gene regulatory networks for human, each specifying the genome-wide connectivity among transcription factors, enhancers, promoters and genes. Integration with 37 genome-wide association studies (GWASs) showed that disease-associated genetic variants—including variants that do not reach genome-wide significance—often perturb regulatory modules that are highly specific to disease-relevant cell types or tissues. Our resource opens the door to systematic analysis of regulatory programs across hundreds of human cell types and tissues (http://regulatorycircuits.org).

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Figure 1: Regulatory circuit inference and GWAS analysis.
Figure 2: Assessment of regulatory circuits.
Figure 3: Network-connectivity enrichment reveals disease-relevant cell types and tissues.

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Acknowledgements

We thank P. Kheradpour (MIT) for providing the collection of curated TF binding motifs. This work was supported by the Swiss National Science Foundation (grant FN 310030_152724/1 to S.B. and grant FN 31003A-143914 to Z.K.), SystemsX.ch (grant SysGenetiX to S.B. and grant AgingX to Z.K.), the Swiss Institute of Bioinformatics (Z.K. and S.B.) and the Leenaards Foundation (Z.K.).

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Authors and Affiliations

  1. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

    Daniel Marbach, David Lamparter & Sven Bergmann

  2. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Daniel Marbach, David Lamparter, Zoltán Kutalik & Sven Bergmann

  3. Broad Institute, MIT, Cambridge, Massachusetts, USA

    Gerald Quon & Manolis Kellis

  4. Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, Massachusetts, USA

    Gerald Quon & Manolis Kellis

  5. Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland

    Zoltán Kutalik

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  1. Daniel Marbach
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  2. David Lamparter
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  3. Gerald Quon
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  4. Manolis Kellis
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  5. Zoltán Kutalik
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Contributions

D.M. designed the study, performed analyses and prepared the manuscript. D.L. performed gene scoring and phenotype-label permutation. D.M., D.L., G.Q., M.K., Z.K. and S.B. conceived methods, discussed the results and implications, and commented on the manuscript at all stages.

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Correspondence to Daniel Marbach.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–47 (PDF 2364 kb)

Supplementary Table 1

Sample annotation (XLSX 108 kb)

Supplementary Table 2

ENCODE ChIP-seq experiments (XLSX 47 kb)

Supplementary Table 3

GTEx tissues (XLSX 42 kb)

Supplementary Table 4

Roadmap Epigenomics RNA-seq data (XLSX 46 kb)

Supplementary Table 5

GWAS compendium (XLSX 16 kb)

Supplementary Table 6

Links to external repositories (XLSX 53 kb)

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Marbach, D., Lamparter, D., Quon, G. et al. Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases. Nat Methods 13, 366–370 (2016). https://doi.org/10.1038/nmeth.3799

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