PMID- 27400856
OWN - NLM
STAT- MEDLINE
DCOM- 20180119
LR  - 20210317
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Print)
IS  - 1359-4184 (Linking)
VI  - 22
IP  - 10
DP  - 2017 Oct
TI  - Genome-wide common and rare variant analysis provides novel insights into 
      clozapine-associated neutropenia.
PG  - 1502-1508
LID - 10.1038/mp.2016.97 [doi]
AB  - 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 x 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.
FAU - Legge, S E
AU  - Legge SE
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Hamshere, M L
AU  - Hamshere ML
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Ripke, S
AU  - Ripke S
AUID- ORCID: 0000-0003-3622-835X
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
AD  - Department of Psychiatry and Psychotherapy, Charite - Universitatsmedizin Berlin, 
      Campus Mitte, Berlin, Germany.
FAU - Pardinas, A F
AU  - Pardinas AF
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Goldstein, J I
AU  - Goldstein JI
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
AD  - Medical and Population Genetics Program, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
FAU - Rees, E
AU  - Rees E
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Richards, A L
AU  - Richards AL
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Leonenko, G
AU  - Leonenko G
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Jorskog, L F
AU  - Jorskog LF
AD  - Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
CN  - Clozapine-Induced Agranulocytosis Consortium
FAU - Chambert, K D
AU  - Chambert KD
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
AD  - Medical and Population Genetics Program, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
AD  - Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, 
      Boston, MA, USA.
FAU - Collier, D A
AU  - Collier DA
AD  - King's College London, SGDP Centre, Institute of Psychiatry, Psychology and 
      Neuroscience, De Crespigny Park, Denmark Hill, London, UK.
AD  - Discovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research 
      Laboratories, Erl Wood Manor, Surrey, UK.
FAU - Genovese, G
AU  - Genovese G
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
FAU - Giegling, I
AU  - Giegling I
AD  - Department of Psychiatry, University of Halle, Halle, Germany.
FAU - Holmans, P
AU  - Holmans P
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Jonasdottir, A
AU  - Jonasdottir A
AD  - deCODE genetics, Sturlugata 8, Reykjavik, Iceland.
FAU - Kirov, G
AU  - Kirov G
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - McCarroll, S A
AU  - McCarroll SA
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
AD  - Department of Genetics, Harvard Medical School, Boston, MA, USA.
FAU - MacCabe, J H
AU  - MacCabe JH
AD  - King's College London, Department of Psychosis Studies, Institute of Psychiatry 
      Psychology and Neuroscience, London, USA.
FAU - Mantripragada, K
AU  - Mantripragada K
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Moran, J L
AU  - Moran JL
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
FAU - Neale, B M
AU  - Neale BM
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
FAU - Stefansson, H
AU  - Stefansson H
AD  - deCODE genetics, Sturlugata 8, Reykjavik, Iceland.
FAU - Rujescu, D
AU  - Rujescu D
AD  - Department of Psychiatry, University of Halle, Halle, Germany.
AD  - Department of Psychiatry, University of Munich, Munich, Germany.
FAU - Daly, M J
AU  - Daly MJ
AD  - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 
      MA, USA.
AD  - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 
      Cambridge, MA, USA.
FAU - Sullivan, P F
AU  - Sullivan PF
AD  - Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
AD  - Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
AD  - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 
      Stockholm, Sweden.
FAU - Owen, M J
AU  - Owen MJ
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - O'Donovan, M C
AU  - O'Donovan MC
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
FAU - Walters, J T R
AU  - Walters JTR
AD  - MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological 
      Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, 
      Cardiff, UK.
LA  - eng
GR  - G0800509/MRC_/Medical Research Council/United Kingdom
GR  - MR/L010305/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/L011794/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/P005748/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20160712
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Carrier Proteins)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (STARD9 protein, human)
RN  - 0 (Solute Carrier Organic Anion Transporter Family Member 1B3)
RN  - J60AR2IKIC (Clozapine)
SB  - IM
EIN - Mol Psychiatry. 2017 Oct;22(10 ):1509. PMID: 27502474
EIN - Mol Psychiatry. 2018 Jan;23 (1):162-163. PMID: 29296025
MH  - Carrier Proteins/genetics
MH  - Case-Control Studies
MH  - Clozapine/*adverse effects/therapeutic use
MH  - Exome
MH  - Female
MH  - Genome-Wide Association Study
MH  - HLA-DQ beta-Chains/genetics
MH  - Humans
MH  - Male
MH  - Neutropenia/*chemically induced/*genetics/metabolism
MH  - Odds Ratio
MH  - Schizophrenia/drug therapy/genetics
MH  - Solute Carrier Organic Anion Transporter Family Member 1B3/genetics
PMC - PMC5065090
MID - EMS68526
COIS- LFJ has received research grant support from Teva/Auspex Pharmaceuticals and has 
      served on a Data Safety and Monitoring Board for Janssen. DAC is a full-time 
      employee and stockholder of Eli Lilly and Company. The remaining authors declare 
      no conflicts of interest.
FIR - Goldstein, Jacqueline I
IR  - Goldstein JI
FIR - Jarskog, L Fredrik
IR  - Jarskog LF
FIR - Hilliard, Chris
IR  - Hilliard C
FIR - Alfirevic, Ana
IR  - Alfirevic A
FIR - Duncan, Laramie
IR  - Duncan L
FIR - Fourches, Denis
IR  - Fourches D
FIR - Huang, Hailiang
IR  - Huang H
FIR - Lek, Monkol
IR  - Lek M
FIR - Neale, Benjamin M
IR  - Neale BM
FIR - Ripke, Stephan
IR  - Ripke S
FIR - Shianna, Kevin
IR  - Shianna K
FIR - Szatkiewicz, Jin P
IR  - Szatkiewicz JP
FIR - Tropsha, Alexander
IR  - Tropsha A
FIR - van den Oord, Edwin Jcg
IR  - van den Oord EJ
FIR - Cascorbi, Ingolf
IR  - Cascorbi I
FIR - Dettling, Michael
IR  - Dettling M
FIR - Gazit, Ephraim
IR  - Gazit E
FIR - Goff, Donald C
IR  - Goff DC
FIR - Holden, Arthur L
IR  - Holden AL
FIR - Kelly, Deanna L
IR  - Kelly DL
FIR - Malhotra, Anil K
IR  - Malhotra AK
FIR - Nielsen, Jimmi
IR  - Nielsen J
FIR - Pirmohamed, Munir
IR  - Pirmohamed M
FIR - Rujescu, Dan
IR  - Rujescu D
FIR - Werge, Thomas
IR  - Werge T
FIR - Levy, Deborah L
IR  - Levy DL
FIR - Josiassen, Richard C
IR  - Josiassen RC
FIR - Kennedy, James L
IR  - Kennedy JL
FIR - Lieberman, Jeffrey A
IR  - Lieberman JA
FIR - Daly, Mark J
IR  - Daly MJ
FIR - Sullivan, Patrick F
IR  - Sullivan PF
EDAT- 2016/07/13 06:00
MHDA- 2018/01/20 06:00
PMCR- 2017/09/30
CRDT- 2016/07/13 06:00
PHST- 2016/01/21 00:00 [received]
PHST- 2016/05/10 00:00 [revised]
PHST- 2016/05/17 00:00 [accepted]
PHST- 2016/07/13 06:00 [pubmed]
PHST- 2018/01/20 06:00 [medline]
PHST- 2016/07/13 06:00 [entrez]
PHST- 2017/09/30 00:00 [pmc-release]
AID - mp201697 [pii]
AID - 10.1038/mp.2016.97 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2017 Oct;22(10):1502-1508. doi: 10.1038/mp.2016.97. Epub 2016 Jul 
      12.