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Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Legge, Sophie E., Hamshere, Marian L., Ripke, S., Pardinas, Antonio, Goldstein, J. I., Rees, Elliott, Richards, Alexander, Leonenko, Ganna M., Jorskog, L. F., Goldstein, Jacqueline I., Jarskog, L Fredrik, Hilliard, Chris, Alfirevic, Ana, Duncan, Laramie, Fourches, Denie, Huang, Hailiang, Lek, Monkol, Neale, Benjamin M, Ripke, Stephan, Shianna, Kevin, Szatkiewicz, Jin P, Tropsha, Alexander, van den Oord, Edwin JCG, Cascorbi, Ingolf, Dettling, Michael, Gazit, Ephraim, Goff, Donald C, Holden, Arthur L, Kelly, Deanna L, Malhotra, Anil K, Nielsen, Jimmi, Pirmohamed, Munir, Rujescu, Dan, Werge, Thomas, Levy, Deborah L, Josiassen, Richard C, Kennedy, James L, Lieberman, Jeffrey A, Daly, Mark J, Sullivan, Patrick F, Chambert, K. D., Collier, D. A., Genovese, G., Giegling, I., Holmans, Peter Alan, Jonasdottir, A., Kirov, George, McCarroll, S. A., MacCabe, J. H., Mantripragada, Kiran Kumar, Moran, J. L., Neale, B. M., Stefansson, H., Rujescu, D., Daly, M. J., Sullivan, P. F., Owen, Michael John, O'Donovan, Michael Conlon and Walters, James Tynan Rhys 2017. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Molecular Psychiatry 22 , pp. 1502-1508. 10.1038/mp.2016.97

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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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: Springer Nature
ISSN: 1359-4184
Date of First Compliant Deposit: 18 July 2016
Date of Acceptance: 17 May 2016
Last Modified: 23 Sep 2019 21:30
URI: http://orca-mwe.cf.ac.uk/id/eprint/92833

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