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).
At a glance
- Identifying and mapping cell-type-specific chromatin programming of gene expression. Proc. Natl. Acad. Sci. USA 111, E645–E654 (2014). &
- Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 6, 5890 (2015). et al.
- A predictive modeling approach for cell line-specific long-range regulatory interactions. Nucleic Acids Res. 43, 8694–8712 (2015). et al.
- Interpreting noncoding genetic variation in complex traits and human disease. Nat. Biotechnol. 30, 1095–1106 (2012). &
- Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl. Acad. Sci. USA 110, 17921–17926 (2013). et al.
- Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013). et al.
- Re-ranking sequencing variants in the post-GWAS era for accurate causal variant identification. PLoS Genet. 9, e1003609 (2013). , , , &
- Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am. J. Hum. Genet. 94, 559–573 (2014).
- Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014). et al.
- The power of protein interaction networks for associating genes with diseases. Bioinformatics 26, 1057–1063 (2010). &
- Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 7, e1001273 (2011). et al.
- Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008). et al.
- Prioritizing candidate disease genes by network-based boosting of genome-wide association data. Genome Res. 21, 1109–1121 (2011). , , , &
- Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. PLoS Genet. 10, e1004502 (2014). et al.
- Sharing and specificity of co-expression networks across 35 human tissues. PLoS Comput. Biol. 11, e1004220 (2015). , , , & the GTEx Consortium.
- Understanding multicellular function and disease with human tissue-specific networks. Nat. Genet. 47, 569–576 (2015). et al.
- Architecture of the human regulatory network derived from ENCODE data. Nature 489, 91–100 (2012). et al.
- Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks. Genome Res. 22, 1334–1349 (2012). et al.
- Coherent functional modules improve transcription factor target identification, cooperativity prediction, and disease association. PLoS Genet. 10, e1004122 (2014). , , &
- Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005). et al.
- A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012). et al.
- Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks. Cell 159, 402–414 (2014). et al.
- The FANTOM Consortium & the RIKEN PMI and CLST (DGT). A promoter-level mammalian expression atlas. Nature 507, 462–470 (2014).
- An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014). et al.
- Systematic dissection of regulatory motifs in 2000 predicted human enhancers using a massively parallel reporter assay. Genome Res. 23, 800–811 (2013). et al.
- Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42, 2976–2987 (2014). &
- Wisdom of crowds for robust gene network inference. Nat. Methods 9, 796–804 (2012). et al.
- The GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
- Roadmap Epigenomics Consortium. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
- Fast and rigorous computation of gene and pathway scores from SNP-based summary statistics. PLoS Comput. Biol. 12, e1004714 (2016). , , , &
- Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J. Neurochem. 113, 287–302 (2010). , &
- The role of the amygdala in bipolar disorder development. Dev. Psychopathol. 20, 1285–1296 (2008). &
- Role of the endothelium in inflammatory bowel diseases. World J. Gastroenterol. 17, 578–593 (2011). , , , &
- Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009). et al.
- Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice. PLoS ONE 5, e12220 (2010). , , &
- The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593–601 (2014). , &
- Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).
- Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat. Genet. 42, 786–789 (2010). et al.
- Human genetics shape the gut microbiome. Cell 159, 789–799 (2014). et al.
- The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
- Reliable prediction of regulator targets using 12 Drosophila genomes. Genome Res. 17, 1919–1931 (2007). , , &
- Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012). et al.
- Revealing strengths and weaknesses of methods for gene network inference. Proc. Natl. Acad. Sci. USA 107, 6286–6291 (2010). et al.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).
- Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).
- Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013). et al.
- A genome-wide association study of anorexia nervosa. Mol. Psychiatry 19, 1085–1094 (2014). et al.
- Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013). et al.
- Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009). et al.
- International Multiple Sclerosis Genetics Consortium. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
- Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011). et al.
- Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010). et al.
- Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010). et al.
- Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138, 1338–1345 (2010). et al.
- Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat. Genet. 43, 333–338 (2011). et al.
- The International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).
- Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).
- Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010). et al.
- A central role for GRB10 in regulation of islet function in man. PLoS Genet. 10, e1004235 (2014). et al.
- The DIAbetes Genetxzics Replication and Meta-analysis (DIAGRAM) Consortium. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).
- Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. 44, 991–1005 (2012). et al.
- Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways. Diabetes 59, 3229–3239 (2010). et al.
- New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105–116 (2010). et al.
- Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2. Diabetes 60, 2624–2634 (2011). et al.
- Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). et al.
- Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010). et al.
- The AMD Gene Consortium. Seven new loci associated with age-related macular degeneration. Nat. Genet. 45, 433–439 (2013).
- Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 44, 491–501 (2012). et al.
- The 1000 Genomes Project: data management and community access. Nat. Methods 9, 459–462 (2012). et al.
- Diffusion kernels on graphs and other discrete input spaces. in Proc. Nineteenth International Conference on Machine Learning 315–322 (Morgan Kaufmann, 2002). &
- Kernels and regularization on graphs. in Learning Theory and Kernel Machines (eds. Schölkopf, B. & Warmuth, M.K.) 144–158 (Springer Berlin Heidelberg, 2003). &
- DADA: degree-aware algorithms for network-based disease gene prioritization. BioData Min. 4, 19 (2011). , , &
- A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat. Biotechnol. 25, 309–316 (2007). et al.
- Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res. 39, D52–D57 (2011). , , &
- The BioGRID interaction database: 2015 update. Nucleic Acids Res. 43, D470–D478 (2015). et al.
- A proteome-scale map of the human interactome network. Cell 159, 1212–1226 (2014). et al.
- Circuitry and dynamics of human transcription factor regulatory networks. Cell 150, 1274–1286 (2012). et al.
- Developing predictive molecular maps of human disease through community-based modeling. Nat. Genet. 44, 127–130 (2012). et al.
- Supplementary Text and Figures (2,421 KB)
Supplementary Figures 1–47
- Supplementary Table 1 (111 KB)
- Supplementary Table 2 (48,953 KB)
ENCODE ChIP-seq experiments
- Supplementary Table 3 (43,164 KB)
- Supplementary Table 4 (47,296 KB)
Roadmap Epigenomics RNA-seq data
- Supplementary Table 5 (17,181 KB)
- Supplementary Table 6 (55,145 KB)
Links to external repositories