title: Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia.
abstract: The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Legge
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Hamshere
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
authors.forename: S
authors.identifier: 0000-0003-3622-835X
authors.initials: S
authors.lastname: Ripke
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Pardinas
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Goldstein
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: E
authors.initials: E
authors.lastname: Rees
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: G
authors.initials: G
authors.lastname: Leonenko
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Jorskog
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Chambert
authors.affiliation: King's College London, SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, Denmark Hill, London, UK.|Discovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research Laboratories, Erl Wood Manor, Surrey, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Giegling
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: P
authors.initials: P
authors.lastname: Holmans
authors.affiliation: deCODE genetics, Sturlugata 8, Reykjavik, Iceland.
authors.forename: A
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: G
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: King's College London, Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, London, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: MacCabe
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: K
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: deCODE genetics, Sturlugata 8, Reykjavik, Iceland.
authors.forename: H
authors.initials: H
authors.lastname: Stefansson
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.|Department of Psychiatry, University of Munich, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.|Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: J T R
authors.initials: JTR
authors.lastname: Walters
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D003024:Clozapine / Q000009:adverse effects* / Q000627:therapeutic use; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D008297:Male; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D016017:Odds Ratio; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C515004:STARD9 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D003024:Clozapine