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

Authors:

  • Soskic B.,
  • Cano-Gamez E.,
  • Smyth D. J.,
  • Rowan W. C.,
  • Nakic N.,
  • Esparza-Gordillo J.,
  • Bossini-Castillo  L.,
  • Tough D. F.,
  • Larminie C. G. C.,
  • Bronson P. G.,
  • Willé D.,
  • Trynka G.

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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