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- Title
Genetic and epigenetic fine mapping of causal autoimmune disease variants.
- Authors
Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang; Kleinewietfeld, Markus; Housley, William J.; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; 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.
- 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.
- Subjects
GENETICS of autoimmune diseases; GENOTYPES; EPIGENETICS; IMMUNE system; GENETIC transcription
- Publication
Nature, 2015, Vol 518, Issue 7539, p337
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13835