Format

Send to

Choose Destination
Nature. 2015 Feb 19;518(7539):337-43. doi: 10.1038/nature13835. Epub 2014 Oct 29.

Genetic and epigenetic fine mapping of causal autoimmune disease variants.

Author information

1
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
2
Diabetes Center and Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, California 94143, USA.
3
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA [3] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [4] Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
4
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
5
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
6
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
7
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
8
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA.
9
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
10
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02142, USA [3] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.
11
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.

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.

PMID:
25363779
PMCID:
PMC4336207
DOI:
10.1038/nature13835
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center