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Genetic and epigenetic fine mapping of causal autoimmune disease variants.

  • Author(s): Farh, Kyle Kai-How
  • Marson, Alexander
  • Zhu, Jiang
  • Kleinewietfeld, Markus
  • Housley, William J
  • Beik, Samantha
  • Shoresh, Noam
  • Whitton, Holly
  • Ryan, Russell JH
  • Shishkin, Alexander A
  • Hatan, Meital
  • Carrasco-Alfonso, Marlene J
  • Mayer, Dita
  • Luckey, C John
  • Patsopoulos, Nikolaos A
  • De Jager, Philip L
  • Kuchroo, Vijay K
  • Epstein, Charles B
  • Daly, Mark J
  • Hafler, David A
  • Bernstein, Bradley E
  • et al.
Abstract

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

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