Evidence map›Paper›PMID 25187353›Full record

ArticleNature communications2014

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Jacqueline I Goldstein, L Fredrik Jarskog, Chris Hilliard, Ana Alfirevic, Laramie Duncan, Denis Fourches, Hailiang Huang, Monkol Lek, Benjamin M Neale, Stephan Ripke and 21 more

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

Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
77citing papers in PubMed, 6 pooled it
13.8field-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

77 citing papers in PubMed, 6 syntheses or guidelines pooled it, 177 citations in OpenAlex.

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  8. Metamizole: Indications and Risks.Deutsches Arzteblatt international · 2026
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  12. Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025
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17 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors at 20 institutions in 7 countries.

Jacqueline I Goldstein1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
L Fredrik JarskogDepartment of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Chris HilliardDepartment of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Ana AlfirevicDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, UK.
Laramie Duncan1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Denis FourchesLaboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Hailiang HuangAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Benjamin M Neale1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [3] Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [4] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Stephan Ripke1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Kevin ShiannaNew York Genome Center, New York, New York 10013, USA.
Jin P SzatkiewiczDepartment of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Alexander TropshaLaboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Edwin J C G van den OordCenter for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Ingolf CascorbiInstitute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
Michael DettlingDepartment of Psychiatry and Psychotherapy, Charité-University Medicine, 14050 Berlin, Germany.
Ephraim GazitTel Aviv University, Ramat Aviv, Tissue Typing Lab, Sheba Medical Center 6997801, Israel.
Donald C GoffDepartment of Psychiatry, New York University, New York New York 10016, USA.
Arthur L HoldenInternational SAE Consortium, Ltd., Chicago, Illinois 60631, USA.
Deanna L KellyMaryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21228, USA.
Anil K Malhotra1] The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA [2] The Hofstra NS-LIJ School of Medicine, Hempstead, New York 11549, USA [3] The Zucker Hillside Hospital, Glen Oaks, New York 11004, USA.
Jimmi Nielsen1] Aalborg University Hospital, Psychiatry, Aalborg 9000, Denmark [2] Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark.
Munir PirmohamedDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, UK.
Dan Rujescu1] Department of Psychiatry, University of Halle, Halle 06112, Germany [2] Department of Psychiatry, University of Munich, 80336 Munich, Germany.
Thomas Werge1] Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark [2] Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Copenhagen 4000, Denmark [3] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8000 Roskilde, Denmark.
Deborah L Levy1] Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts 02478, USA.
Richard C JosiassenDepartment of Psychiatry, Drexel University, Philadelphia, Pennsylvania 19104, USA.
James L KennedyCenter for Addiction and Mental Health, Toronto, Canada M5T 1R8.
Jeffrey A LiebermanDepartment of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York, New York 10032, USA.
Mark J Daly1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [3].
Patrick F Sullivan1] Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden [4].
Massachusetts General Hospital · USUniversity of North Carolina at Chapel Hill · USUniversity of Liverpool · GBAalborg University · DKBroad Institute · USCentre for Addiction and Mental Health · CACharité - Universitätsmedizin Berlin · DEDrexel University · USFeinstein Institute for Medical Research · USLudwig-Maximilians-Universität München · DEMcLean Hospital · USMental Health Services · DKNew York Genome Center · USNew York State Psychiatric InstituteNew York University · USSheba Medical Center · ILSociety of Automotive Engineers International · USUniversity of Lübeck · DEUniversity of Maryland, Baltimore · USVirginia Commonwealth University · US

Funding

2/2 A genome-wide association study to detect genetic variation for schizophreniaR01MH080403 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SULLIVAN, PATRICK F · 2008 to 2010
$4.5M
2/2-Cis & Trans-Data Integration to Find Mechanisms Causing Psychiatric DisordersR01MH097281 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SULLIVAN, PATRICK F · 2012 to 2014
$740k
Medical Research Council MR/L006758/1NIMH NIH HHS R01 MH080403NIMH NIH HHS R01 MH097281
6 · The paper itself

Abstract

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Indexed as

ExomeGenetic Predisposition to DiseaseAgranulocytosisAllelesAmino Acid SubstitutionAntipsychotic AgentsCase-Control StudiesClozapineGene FrequencyGenome-Wide Association StudyHeterozygoteHLA-B AntigensHLA-DQ beta-ChainsHumansOdds RatioPsychotic DisordersAntipsychotic AgentsClozapineHLA-B AntigensHLA-DQB1 antigenHLA-DQ beta-Chains

Identifiers

PMID25187353
PMCPMC4155508
OpenAlexW2140165667

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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.