Publication Date:
2014-11-05
Description:
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 approximately 90% of causal variants are non-coding, with approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336207/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336207/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- Bernstein, Bradley E -- 12-0089/Worldwide Cancer Research/United Kingdom -- AI039671/AI/NIAID NIH HHS/ -- AI045757/AI/NIAID NIH HHS/ -- AI046130/AI/NIAID NIH HHS/ -- AI070352/AI/NIAID NIH HHS/ -- ES017155/ES/NIEHS NIH HHS/ -- GM093080/GM/NIGMS NIH HHS/ -- HG004570/HG/NHGRI NIH HHS/ -- NS067305/NS/NINDS NIH HHS/ -- NS24247/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 NS024247/NS/NINDS NIH HHS/ -- R37 NS024247/NS/NINDS NIH HHS/ -- T32 GM007748/GM/NIGMS NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U19 AI046130/AI/NIAID NIH HHS/ -- U19 AI070352/AI/NIAID NIH HHS/ -- U54 HG004570/HG/NHGRI NIH HHS/ -- U54 HG006991/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 19;518(7539):337-43. doi: 10.1038/nature13835. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Diabetes Center and Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, California 94143, USA. ; 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. ; 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. ; Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 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. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA. ; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; 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. ; Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363779" target="_blank"〉PubMed〈/a〉
Keywords:
Autoimmune Diseases/*genetics/immunology/pathology
;
Base Sequence
;
Chromatin/genetics
;
Consensus Sequence/genetics
;
Enhancer Elements, Genetic/genetics
;
Epigenesis, Genetic/*genetics
;
Epigenomics
;
Genome-Wide Association Study
;
Humans
;
Nucleotide Motifs
;
Organ Specificity
;
Polymorphism, Single Nucleotide/*genetics
;
T-Lymphocytes/immunology/metabolism
;
Transcription Factors/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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