title: Genetic and epigenetic fine mapping of causal autoimmune disease variants.
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.
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Kyle Kai-How
authors.initials: KK
authors.lastname: Farh
authors.affiliation: Diabetes Center and Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, California 94143, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marson
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Kleinewietfeld
authors.affiliation: Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Housley
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Beik
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Noam
authors.initials: N
authors.lastname: Shoresh
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Whitton
authors.affiliation: 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.
authors.forename: Russell J H
authors.initials: RJ
authors.lastname: Ryan
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shishkin
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Meital
authors.initials: M
authors.lastname: Hatan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Carrasco-Alfonso
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dita
authors.initials: D
authors.lastname: Mayer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: C John
authors.initials: CJ
authors.lastname: Luckey
authors.affiliation: 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.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: 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.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Epstein
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.affiliation: 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.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D002843:Chromatin / Q000235:genetics; D016384:Consensus Sequence / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D055106:Genome-Wide Association Study; D006801:Humans; D059372:Nucleotide Motifs; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D014157:Transcription Factors