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, Kevin Shianna, Jin P. Szatkiewicz, Alexander Tropsha, Edwin JCG van den Oord, Ingolf Cascorbi, Michael Dettling, Ephraim Gazit, Donald C. Goff, Arthur L. Holden, Deanna L. Kelly, Anil K. Malhotra, Jimmi Nielsen, Munir Pirmohamed, Dan Rujescu, Thomas Werge, Deborah L. Levy, Richard C. Josiassen, James L. Kennedy, Jeffrey A. Lieberman, Mark J. Daly () and Patrick F. Sullivan ()
Additional contact information
Jacqueline I. Goldstein: Analytic and Translational Genetics Unit, Massachusetts General Hospital
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
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
Stephan Ripke: Analytic and Translational Genetics Unit, Massachusetts General Hospital
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
Jimmi Nielsen: Aalborg University Hospital, Psychiatry
Munir Pirmohamed: University of Liverpool
Dan Rujescu: University of Halle
Thomas Werge: University of Copenhagen
Deborah L. Levy: Harvard Medical School
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
Patrick F. Sullivan: University of North Carolina

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5757

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