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

Author

Listed:
  • Jacqueline I. Goldstein

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • L. Fredrik Jarskog

    (University of North Carolina)

  • Chris Hilliard

    (University of North Carolina)

  • Ana Alfirevic

    (University of Liverpool)

  • Laramie Duncan

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Denis Fourches

    (Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina)

  • Hailiang Huang

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital)

  • Monkol Lek

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital)

  • Benjamin M. Neale

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard
    Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Stephan Ripke

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard)

  • Kevin Shianna

    (New York Genome Center)

  • Jin P. Szatkiewicz

    (University of North Carolina)

  • Alexander Tropsha

    (Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina)

  • Edwin JCG van den Oord

    (Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University)

  • Ingolf Cascorbi

    (Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein)

  • Michael Dettling

    (Charité-University Medicine)

  • Ephraim Gazit

    (Tel Aviv University)

  • Donald C. Goff

    (New York University)

  • Arthur L. Holden

    (International SAE Consortium, Ltd.)

  • Deanna L. Kelly

    (Maryland Psychiatric Research Center, University of Maryland)

  • Anil K. Malhotra

    (The Feinstein Institute for Medical Research
    The Hofstra NS-LIJ School of Medicine
    The Zucker Hillside Hospital)

  • Jimmi Nielsen

    (Aalborg University Hospital, Psychiatry
    Aalborg University)

  • Munir Pirmohamed

    (University of Liverpool)

  • Dan Rujescu

    (University of Halle
    University of Munich)

  • Thomas Werge

    (University of Copenhagen
    Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen
    The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH)

  • Deborah L. Levy

    (Harvard Medical School
    Psychology Research Laboratory, McLean Hospital)

  • Richard C. Josiassen

    (Drexel University)

  • James L. Kennedy

    (Center for Addiction and Mental Health)

  • Jeffrey A. Lieberman

    (Columbia University and the New York State Psychiatric Institute)

  • Mark J. Daly

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Medical and Population Genetics Program, Broad Institute of MIT and Harvard)

  • Patrick F. Sullivan

    (University of North Carolina
    University of North Carolina
    Karolinska Institutet)

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.

Suggested Citation

  • Jacqueline I. Goldstein & L. Fredrik Jarskog & Chris Hilliard & Ana Alfirevic & Laramie Duncan & Denis Fourches & Hailiang Huang & Monkol Lek & Benjamin M. Neale & Stephan Ripke & Kevin Shianna & Jin , 2014. "Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5757
    DOI: 10.1038/ncomms5757
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