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 J  C G 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; Patrick F Sullivan

doi:10.1038/ncomms5757

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

Nat Commun. 2014 Sep 4:5:4757. doi: 10.1038/ncomms5757.

Authors

Jacqueline I Goldstein¹, L Fredrik Jarskog², Chris Hilliard², Ana Alfirevic³, Laramie Duncan¹, Denis Fourches⁴, Hailiang Huang⁵, Monkol Lek⁵, Benjamin M Neale⁶, Stephan Ripke⁷, Kevin Shianna⁸, Jin P Szatkiewicz⁹, Alexander Tropsha⁴, Edwin J C G van den Oord¹⁰, Ingolf Cascorbi¹¹, Michael Dettling¹², Ephraim Gazit¹³, Donald C Goff¹⁴, Arthur L Holden¹⁵, Deanna L Kelly¹⁶, Anil K Malhotra¹⁷, Jimmi Nielsen¹⁸, Munir Pirmohamed³, Dan Rujescu¹⁹, Thomas Werge²⁰, Deborah L Levy²¹, Richard C Josiassen²², James L Kennedy²³, Jeffrey A Lieberman²⁴, Mark J Daly²⁵, Patrick F Sullivan²⁶

Affiliations

¹ 1] 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.
² Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
³ Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, UK.
⁴ Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁶ 1] 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.
⁷ 1] 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.
⁸ New York Genome Center, New York, New York 10013, USA.
⁹ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
¹⁰ Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
¹¹ Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
¹² Department of Psychiatry and Psychotherapy, Charité-University Medicine, 14050 Berlin, Germany.
¹³ Tel Aviv University, Ramat Aviv, Tissue Typing Lab, Sheba Medical Center 6997801, Israel.
¹⁴ Department of Psychiatry, New York University, New York New York 10016, USA.
¹⁵ International SAE Consortium, Ltd., Chicago, Illinois 60631, USA.
¹⁶ Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21228, USA.
¹⁷ 1] 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.
¹⁸ 1] Aalborg University Hospital, Psychiatry, Aalborg 9000, Denmark [2] Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark.
¹⁹ 1] Department of Psychiatry, University of Halle, Halle 06112, Germany [2] Department of Psychiatry, University of Munich, 80336 Munich, Germany.
²⁰ 1] 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.
²¹ 1] Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts 02478, USA.
²² Department of Psychiatry, Drexel University, Philadelphia, Pennsylvania 19104, USA.
²³ Center for Addiction and Mental Health, Toronto, Canada M5T 1R8.
²⁴ Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York, New York 10032, USA.
²⁵ 1] 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].
²⁶ 1] 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].

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.

Publication types

Multicenter Study
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Agranulocytosis / chemically induced
Agranulocytosis / genetics*
Agranulocytosis / immunology
Alleles
Amino Acid Substitution
Antipsychotic Agents / adverse effects*
Case-Control Studies
Clozapine / adverse effects*
Exome*
Gene Frequency
Genetic Predisposition to Disease*
Genome-Wide Association Study
HLA-B Antigens / genetics*
HLA-B Antigens / immunology
HLA-DQ beta-Chains / genetics*
HLA-DQ beta-Chains / immunology
Heterozygote
Humans
Odds Ratio
Psychotic Disorders / drug therapy
Psychotic Disorders / genetics
Psychotic Disorders / immunology
Severity of Illness Index

Substances

Antipsychotic Agents
HLA-B Antigens
HLA-DQ beta-Chains
HLA-DQB1 antigen
Clozapine

Abstract

Publication types

MeSH terms

Substances

Grants and funding