Evidence map›Paper›PMID 25363779›Full record

ArticleNature2015

Genetic and epigenetic fine mapping of causal autoimmune disease variants.

Kyle Kai-How Farh, Alexander Marson, Jiang Zhu, Markus Kleinewietfeld, William J Housley, Samantha Beik, Noam Shoresh, Holly Whitton, Russell J H Ryan, Alexander A Shishkin and 11 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,159 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
1,159citing papers in PubMed, 5 pooled it
71.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1,159 citing papers in PubMed, 5 syntheses or guidelines pooled it, 2,124 citations in OpenAlex.

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  16. Where risk resides.Nature immunology · 2026
    Article
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1,099 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors at 5 institutions in 1 country.

Kyle Kai-How Farh1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Alexander MarsonDiabetes Center and Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, California 94143, USA.
Jiang Zhu1] 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.
Markus Kleinewietfeld1] 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.
William J HousleyDepartments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06511, USA.
Samantha BeikBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Noam ShoreshBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Holly WhittonBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Russell J H Ryan1] 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.
Alexander A Shishkin1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] California Institute of Technology, 1200 E California Boulevard, Pasadena, California 91125, USA.
Meital HatanBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Marlene J Carrasco-AlfonsoDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Dita MayerDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
C John LuckeyDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nikolaos A Patsopoulos1] 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.
Philip L De Jager1] 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.
Vijay K KuchrooCenter for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA.
Charles B EpsteinBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Mark J Daly1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
David A Hafler1] 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.
Bradley E Bernstein1] 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.
Broad Institute · USHarvard University · USBrigham and Women's Hospital · USYale University · USUniversity of California, San Francisco · US

Funding

Role of Negative Costimulation in Regulation of AutoimmunityP01AI039671 · NIAID · YALE UNIVERSITY · PI David A. Hafler · 1996 to 2026
$51.7M
TCR recognition of MHC class II peptide compexes in multiple sclerosisP01AI045757 · NIAID · DANA-FARBER CANCER INSTITUTE · PI WUCHERPFENNIG, KAI W · 1999 to 2017
$22.8M
Research BaseP30DK063720 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KRUMMEL, MATTHEW F · 2003 to 2019
$21.8M
Production sequencing of reference human epigenomesU01ES017155 · NIEHS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BERNSTEIN, BRADLEY EVAN, MEISSNER, ALEXANDER · 2008 to 2012
$15.4M
INTERDISCIPLINARY IMMUNOLOGY TRAINING PROGRAMT32AI007019 · NIAID · YALE UNIVERSITY · PI Carrie L. Lucas, David G. Schatz · 1985 to 2026
$14.4M
TRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0M
High-throughput sequencing of chromatin regulatory elementsU54HG004570 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BERNSTEIN, BRADLEY EVAN · 2007 to 2011
$8.1M
Expanding the catalog of chromatin regulatory elements in the human genomeU54HG006991 · NHGRI · BROAD INSTITUTE, INC. · PI BERNSTEIN, BRADLEY EVAN · 2012 to 2016
$7.9M
Gene Expression and Regulatory Networks in Human LeukocytesRC2GM093080 · NIGMS · HARVARD MEDICAL SCHOOL · PI BENOIST, CHRISTOPHE O., MATHIS, DIANE J · 2009 to 2010
$7.3M
Regulatory T Cells in Autoimmune DiseaseU19AI070352 · NIAID · YALE UNIVERSITY · PI HAFLER, DAVID A. · 2006 to 2011
$5.9M
Treatment of Autoimmune Disease by Costimulatory Signal*U19AI046130 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WILSON, S. BRIAN BRIAN · 1999 to 2007
$5.6M
T Cell Recognition of Myelin in Multiple SclerosisR37NS024247 · NINDS · YALE UNIVERSITY · PI HAFLER, DAVID A. · 2004 to 2010
$2.8M
Howard Hughes Medical InstituteNHGRI NIH HHS HG004570NHGRI NIH HHS U54 HG004570NHGRI NIH HHS U54 HG006991NIAID NIH HHS AI039671NIAID NIH HHS AI045757NIAID NIH HHS AI046130NIAID NIH HHS AI070352NIAID NIH HHS P01 AI039671NIAID NIH HHS P01 AI045757NIAID NIH HHS T32 AI007019NIAID NIH HHS U19 AI046130NIAID NIH HHS U19 AI070352NIDDK NIH HHS P30 DK063720NIEHS NIH HHS ES017155NIEHS NIH HHS U01 ES017155NIGMS NIH HHS GM093080NIGMS NIH HHS RC2 GM093080NIGMS NIH HHS T32 GM007748NINDS NIH HHS NS067305NINDS NIH HHS NS24247NINDS NIH HHS R01 NS024247NINDS NIH HHS R01 NS067305NINDS NIH HHS R37 NS024247
6 · The paper itself

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.

Indexed as

Autoimmune DiseasesBase SequenceChromatinConsensus SequenceEnhancer Elements, GeneticEpigenesis, GeneticEpigenomicsGenome-Wide Association StudyHumansNucleotide MotifsOrgan SpecificityPolymorphism, Single NucleotideT-LymphocytesTranscription FactorsChromatinTranscription Factors

Identifiers

PMID25363779
PMCPMC4336207
OpenAlexW2056198580

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.