title: Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.
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.
authors.affiliation: 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.
authors.forename: Jacqueline I
authors.initials: JI
authors.lastname: Goldstein
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: L Fredrik
authors.initials: LF
authors.lastname: Jarskog
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Hilliard
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.affiliation: 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.
authors.forename: Laramie
authors.initials: L
authors.lastname: Duncan
authors.affiliation: 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Fourches
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: 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.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: New York Genome Center, New York, New York 10013, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shianna
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jin P
authors.initials: JP
authors.lastname: Szatkiewicz
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
authors.affiliation: Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Edwin J  C G
authors.initials: EJ
authors.lastname: van den Oord
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.affiliation: Department of Psychiatry and Psychotherapy, Charité-University Medicine, 14050 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dettling
authors.affiliation: Tel Aviv University, Ramat Aviv, Tissue Typing Lab, Sheba Medical Center 6997801, Israel.
authors.forename: Ephraim
authors.initials: E
authors.lastname: Gazit
authors.affiliation: Department of Psychiatry, New York University, New York New York 10016, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Goff
authors.affiliation: International SAE Consortium, Ltd., Chicago, Illinois 60631, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Holden
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21228, USA.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kelly
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.affiliation: 1] Aalborg University Hospital, Psychiatry, Aalborg 9000, Denmark [2] Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark.
authors.forename: Jimmi
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: 1] Department of Psychiatry, University of Halle, Halle 06112, Germany [2] Department of Psychiatry, University of Munich, 80336 Munich, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.affiliation: 1] Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Psychology Research Laboratory, McLean Hospital, Belmont, Massachusetts 02478, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Levy
authors.affiliation: Department of Psychiatry, Drexel University, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Josiassen
authors.affiliation: Center for Addiction and Mental Health, Toronto, Canada M5T 1R8.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York, New York 10032, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: 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].
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: 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].
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
mesh_terms: D000380:Agranulocytosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D000483:Alleles; D019943:Amino Acid Substitution; D014150:Antipsychotic Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects*; D059472:Exome; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D016017:Odds Ratio; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index
chemical_list: D014150:Antipsychotic Agents; D015235:HLA-B Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D003024:Clozapine