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A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia

Abstract

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (β = −0.9, P = 4.21 × 10−21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10−7). This genotype, also termed “Duffy-null”, has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.

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Conflict of interest

DAC is a full-time employee and stockholder of Eli Lilly and Company. MH, JAJ and KJ are full-time employees of Leyden Delta B.V. The remaining authors declare that they have no conflict of interest.

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Acknowledgements

This project was supported by Medical Research Council (MRC) Centre (MR/L010305/1), Program (G0800509) and Project ("STRATA", MR/L011794/1) grants to Cardiff University. The project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 279227 (CRESTAR Consortium; http://www.crestar-project.eu/). This publication reflects only the authors’ views and the European Union is not liable for any use that may be made of the information contained therein. We acknowledge Leyden Delta and Magna Laboratories, UK, for supporting the CLOZUK2 sample collection, anonymisation and data preparation (Andy Walker and Anouschka Colson). We acknowledge deCODE genetics (Hreinn Stefansson and colleagues) for genotyping of the CLOZUK2 sample. We acknowledge the MRC Centre laboratory staff (particularly Lucinda Hopkins, Lesley Bates and Catherine Bresner) at Cardiff University for laboratory sample management and Wayne Lawrence and Mark Einon at Cardiff University for support with the use and setup of computational infrastructures.

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Conflict of interest

DAC is a full-time employee and stockholder of Eli Lilly and Company. MH, JAJ and KJ are full-time employees of Leyden Delta B.V. The remaining authors declare that they have no conflict of interest.

Correspondence to James T. R. Walters.

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