Genetic and epigenetic fine mapping of causal autoimmune disease variants
Top Cited Papers
Open Access
- 29 October 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 518 (7539), 337-343
- https://doi.org/10.1038/nature13835
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.Keywords
This publication has 67 references indexed in Scilit:
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- A Validated Regulatory Network for Th17 Cell SpecificationCell, 2012
- Foxp3 Exploits a Pre-Existent Enhancer Landscape for Regulatory T Cell Lineage SpecificationCell, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Architecture of the human regulatory network derived from ENCODE dataNature, 2012
- T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elementsNature Communications, 2012
- Functional and Mechanistic Diversity of Distal Transcription EnhancersCell, 2011
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- TGF-β: A Master of All T Cell TradesCell, 2008
- Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammalsNature, 2005