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Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases

Nature Genetics volume 51, pages 1486–1493 (2019)Cite this article

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Abstract

Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4+ T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (TH1) cells, whereas variants associated with Alzheimer’s disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages.

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Fig. 1: Quantitative changes in chromatin activity distinguish immune cell states.
Fig. 2: Overview of the CHEERS method.
Fig. 3: Enrichment of disease-associated SNPs in H3K27ac regions in cytokine-induced cell states.
Fig. 4: Example loci that drive the enrichment of SNPs associated with immune diseases in cytokine-induced cell states.

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Data availability

All of the raw-sequencing files are deposited in the EGA. ATAC-seq data are available at EGAS00001003501. H3K27ac data are available at EGAS00001002749.

Code availability

CHEERS code is available through GitHub (https://github.com/trynkaLab/CHEERS).

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Acknowledgements

This work was funded by the Open Targets grant (OTAR040) awarded to G.T. G.T. is supported by the Wellcome Trust (grant WT206194). E.C.-G. is supported by a Gates Cambridge Scholarship (OPP1144). L.B.-C. is supported by the MRC Skills Development Fellowship (MR/N014995/1).

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Author notes

  1. These authors contributed equally: Blagoje Soskic, Eddie Cano-Gamez.

Authors and Affiliations

  1. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

    Blagoje Soskic, Eddie Cano-Gamez, Deborah J. Smyth, Lara Bossini-Castillo & Gosia Trynka

  2. Open Targets, Wellcome Genome Campus, Cambridge, UK

    Blagoje Soskic, Eddie Cano-Gamez, Deborah J. Smyth & Gosia Trynka

  3. Novel Human Genetics, GSK Research, GSK Medicines Research Centre, Stevenage, UK

    Wendy C. Rowan

  4. Functional Genomics, Molecular Science and Technology R&D, GSK Medicines Research Centre, Stevenage, UK

    Nikolina Nakic

  5. Human Genetics, GSK Research, GSK Medicines Research Centre, Stevenage, UK

    Jorge Esparza-Gordillo & Christopher G. C. Larminie

  6. Epigenetics RU, Oncology R&D, GSK Medicines Research Centre, Stevenage, UK

    David F. Tough

  7. Human Target Validation Core, RED Translational Biology, Biogen, Cambridge, MA, USA

    Paola G. Bronson

  8. Biostatistics, GSK Research, GSK Medicines Research Centre, Stevenage, UK

    David Willé

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Contributions

G.T. and B.S. conceived and designed the project. B.S., E.C.-G. and D.J.S. carried out the experimental work. B.S. and E.C.-G. performed the data analysis. B.S., E.C.-G., G.T., W.C.R., N.N., J.E.-G., D.F.T., C.G.C.L., D.W., L.B.-C. and P.G.B. interpreted the results. B.S., D.W., E.C.-G. and G.T. developed the CHEERS method. L.B.-C. calculated LD blocks. G.T. supervised the analysis. G.T., B.S., E.C.-G., W.C.R., N.N., J.E.-G., D.F.T., C.G.C.L., D.W. and P.G.B. wrote the manuscript.

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Correspondence to Gosia Trynka.

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Supplementary Fig. 1 Quality control of ATAC and H3K27ac data.

a) Purity of naive T cells (CD4+CD45RA+), memory T cells (CD4+CD45RO+) and macrophages. Representative plots were from three biologically independent samples in T cells and two biologically independent samples in macrophages. b) Number of reads, number of peaks, fraction of reads in peaks (FRiP) and mean q-value of H3K27ac and ATAC peaks. Peak q-values were determined using MACS2. Number of samples in H3K27ac is: 38 (naive_16h), 35 (naive_5d), 32 (memory_16h), 35 (memory_5d), 16 (macrophage_6h) and 17 (macrophage_24h). Number of samples in ATAC is: 36 (naive_16h), 31 (naive_5d), 34 (memory_16h), 28 (memory_5d), 19 (macrophage_6h) and 20 (macrophage_24h). Minima, maxima, centre, and percentiles are reported in Supplementary Table 2. c) Number of peaks in resting and stimulated naive and memory T cells. Stimulated cells were cultured with anti-CD3/anti-CD28 beads. Number of samples in H3K27ac is: 15 (resting) and 125 (stimulated). Number of samples in ATAC is: 10 (resting) and 119 (stimulated). We performed two tailed t-test (ChM: t = 4.58, df = 25.1, p-value = 0.0001; ATAC: t = 0.87, df = 10.55, p-value = 0.41). Minima, maxima, centre, and percentiles are reported in Supplementary table 2. d) Percentage of reproducible peaks per condition. Reproducible peaks are peaks that were observed in at least two biological replicates of the same condition. Number of samples in H3K27ac and ATAC is the same as in panel B. Minima, maxima, centre, and percentiles are reported in Supplementary table 2. e) Comparison of read counts in peaks between biologically independent samples (between individuals) and 15 technical replicates (within an individual) included in our study. The red line represents the mean R2.

Supplementary Fig. 2 Chromatin regulatory landscape in cytokine induced immune cell states captured by H3K27ac ChM-seq and ATAC-seq.

a) Distribution of ATAC and H3K27ac peak length. b) Distribution of ATAC and H3K27ac peaks relative to TSS. c) Proportion of ATAC and H3K27ac in different genomic annotations. d) Overlap between ATAC and H3K27ac peaks (upper panel) and of the genes in proximity to peaks (bottom panel). e) Pathway enrichment analysis using genes in proximity to the top and bottom 1% variable H3K27ac peaks. P-values were calculated using g:ProfileR with default parameters. The number of genes used for the enrichment analysis was 1,156 (nearby top variable peaks) and 1,253 (nearby bottom variable peaks).

Supplementary Fig. 3 PCA of H3K27ac and ATAC data.

a) PCA using H3K27ac and b) ATAC-seq data across all cell types and cell states within the study (left), and T cells only (right). Each sample is colored by broad cell lineage, while the color shade represents duration of activation. Circles represent resting cells and triangles correspond to stimulated cells. PCA plots were derived using 73 naive T cells, 67 memory T cells and 33 macrophage states for H3K27ac (a) and 67 naive T cells, 62 memory T cells and 39 macrophage states for ATAC (b). c) PCA of T cells using reads in H3K27ac peaks within cell type and stimulation time point. PCA plots were derived using 31 naive D5 T cells, 29 memory D5 T cells, 14 macrophages stimulated for 6h and 15 macrophages stimulated for 24h cell states.

Supplementary Fig. 4 ATAC-seq read pile-ups at hallmark loci for cytokine induced cell states.

ATAC-seq read pile ups in regions proximal to condition specific hallmark genes: CD3 (T cells), CD14 (macrophages), KI67 (T cell activation), TBX21 (Th1), GATA3 (Th2), IL35B (that is EBI3, iTreg), IFIT2 (IFN-induced). Genomic coordinates (GRCh38) for each gene are labeled. ATAC-seq tracks were generated after merging three biologically independent samples per cell state.

Supplementary Fig. 5 Binary SNP-peak overlap does not discriminate between closely related cell states.

We used GoShifter to test for SNP enrichment across cytokine induced cell states. GoShifter was performed after merging three biologically independent samples per cell state. P-values were calculated using 10,000 permutations implemented in GoShifter.

Supplementary Fig. 6 Power calculations for CHEERS.

Colors represent percentile of top cell state peak specificity ranks which were sampled to compute power of detecting significant enrichment under different percentages (x-axis) of SNPs mapping in these top peaks.

Supplementary Fig. 7 Disease SNP enrichment in H3K27ac regions in blood cell types from the BLUEPRINT and ROADMAP projects.

a) One-sided p-values are reported from a discrete uniform distribution. CHEERS was performed after merging one to six biological replicates per cell type (sample sizes are shown in Supplementary Table 2) resulting in 236,222 peaks. GWAS data and the statistical methods are described in the “GWAS data processing” and “CHEERS” sections of the Methods. The dotted gray line marks the nominal p-value threshold of 0.05, while the solid gray line represents the Bonferroni-corrected significance threshold (p-value ≤ 0.0026). b) Correlation of -log10(p-values) across diseases. Pearson’s correlations between 13 diseases were calculated using 20 cell types. c) Proportion of peaks shared by multiple immune cell types (barplot) and coefficient of variation of read counts per peak between cell types in the BLUEPRINT data. Number of peaks is 236,222. d) One-sided p-values are reported from a discrete uniform distribution. CHEERS was performed on one sample resulting in 174,296 peaks. GWAS data and the statistical method are described in the “GWAS data processing” and “CHEERS” sections of the Methods.

Supplementary Fig. 8 Disease SNP enrichment in TSS proximal and distal H3K27ac regions.

One-sided p-values are reported from a discrete uniform distribution. CHEERS was performed after merging three biologically independent samples. GWAS data and the statistical method are described in the “GWAS data processing” and “CHEERS” sections of the Methods. The dotted gray line marks the nominal p-value threshold of 0.05, while the solid gray line represents the Bonferroni-corrected significance threshold (p-value ≤ 9 x 10-4). A) Enrichment using proximal (≤5kb from TSS, 79,419 peaks) and B) distal peaks (>5kb from TSS, 48,305 peaks).

Supplementary Fig. 9 Clustering by cell state specificity score of peaks overlapping SNPs associated with Crohn’s disease, rheumatoid arthritis and Alzheimer’s disease.

a) Each row corresponds to a H3K27ac peak, while each column corresponds to a cytokine induced cell state. Shades of blue represent specificity of a peak (specificity rank of a peak normalized to the mean specificity rank of all peaks). b,c,d) Genomic coordinates (GRCh38) for each gene are labeled. H3K27ac tracks are generated after merging three biologically independent samples per cell state. b) Read pileups of H3K27ac (blue) and ATAC-seq (red) peaks at loci driving the enrichment of allergy variants in T cell activation. c) Read pileups of H3K27ac (blue) and ATAC-seq (red) peaks at loci driving the enrichment of RA variants in T cell activation. d) Read pileups of H3K27ac (blue) and ATAC-seq (red) peaks at loci driving the enrichment of IBD variants in Th1 cells.

Supplementary Fig. 10 CHEERS SNP enrichment in ATAC-seq defined regions in cytokine induced cell states.

a) One-sided p-values are reported from a discrete uniform distribution. CHEERS was performed after merging three biologically independent samples resulting in 136,692 peaks. GWAS data and the statistical method are described in the “GWAS data processing” and “CHEERS” sections of the Methods. The dotted gray line marks the nominal p-value threshold of 0.05, while the solid gray line represents the Bonferroni-corrected significance threshold (p-value ≤ 9 x 10-4). b) Correlation of 55 p-value ranks from CHEERS SNP enrichments obtained using H3K27ac and ATAC-seq. The grey line depicts the identity line. Pearson’s correlation coefficient (PCC) is provided below each disease label.

Supplementary Fig. 11 Disease SNP enrichment in TSS proximal and distal ATAC peaks.

One-sided p-values are reported from a discrete uniform distribution. CHEERS was performed after merging three biologically independent samples. GWAS data and the statistical method are described in the “GWAS data processing” and “CHEERS” sections of the Methods. The dotted gray line marks the nominal p-value threshold of 0.05, while the solid gray line represents the Bonferroni-corrected significance threshold (p-value ≤ 9 x 10-4). A) CHEERS was performed on proximal ATAC peaks (≤ 5kb from TSS, 88,150 peaks). B) CHEERS was performed on distal peaks (> 5kb from TSS, 48,543 peaks).

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–11

Reporting Summary

Supplementary Table 1

Cytokine concentrations.

Supplementary Table 2

Sample sizes and violin plot details.

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Soskic, B., Cano-Gamez, E., Smyth, D.J. et al. Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases. Nat Genet 51, 1486–1493 (2019). https://doi.org/10.1038/s41588-019-0493-9

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