Genetic and epigenetic fine mapping of causal autoimmune disease variants.
Farh, Kyle Kai-How a1,a2,n1,a10; Marson, Alexander a3,c1,n1; Zhu, Jiang a1,a4,a5,a6; Kleinewietfeld, Markus a1,a7,n2; Housley, William J. a7; Beik, Samantha a1; Shoresh, Noam a1; Whitton, Holly a1; Ryan, Russell J. H. a1,a5; Shishkin, Alexander A. a1,a8; Hatan, Meital a1; Carrasco-Alfonso, Marlene J. a9; Mayer, Dita a9; Luckey, John C. a9; Patsopoulos, Nikolaos A. a1,a10,a11; De Jager, Philip L. a1,a10,a11,a2,a23,a34; Kuchroo, Vijay K. a12; Epstein, Charles B. a1; Daly, Mark J. a1,a2; Hafler, David A. a1,a7,n3
[Article] Nature. 518(7539):337-343, February 19, 2015.

(Format: HTML, PDF)

: 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.

(C) 2015 Nature Publishing Group