Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Psychiatry and Mental health,Molecular Biology
Reference43 articles.
1. Kane J, Honigfeld G, Singer J, Meltzer H . Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796.
2. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM . Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31–41.
3. Royal College of Psychiatrists. Report of the National Audit of Schizophrenia (NAS) 2012. Healthcare Quality Improvement Partnership, London, 2012.
4. Atkin K, Kendall F, Gould D, Freeman H, Liberman J, O'Sullivan D . Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry 1996; 169: 483–488.
5. Patel MX . Clinician hesitation prior to clozapine initiation: is it justifiable? Br J Psychiatry 2012; 201: 425–427.
Cited by
55 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献