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



Legge, SE, Hamshere, ML, Ripke, S ORCID: 0000-0003-3622-835X, Pardinas, AF, Goldstein, JI, Rees, E, Richards, AL, Leonenko, G, Jorskog, LF, Chambert, KD
et al (show 18 more authors) (2017) Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Molecular Psychiatry, 22 (10). 1502 - 1508.

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Abstract

<jats:title>Abstract</jats:title> <jats:p>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, <jats:italic>P</jats:italic>=1.79 × 10<jats:sup>−8</jats:sup>), intronic to transcripts of <jats:italic>SLCO1B3</jats:italic> and <jats:italic>SLCO1B7</jats:italic>, 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 <jats:italic>UBAP2</jats:italic> and <jats:italic>STARD9</jats:italic>. We additionally provide independent replication of a previously identified variant in <jats:italic>HLA-DQB1</jats:italic> (OR=15.6, <jats:italic>P</jats:italic>=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.</jats:p>

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 18 Oct 2016 15:28
Last Modified: 05 May 2021 07:10
DOI: 10.1038/mp.2016.97
URI: https://livrepository.liverpool.ac.uk/id/eprint/3003181