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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

Legge, Sophie E., Pardinas, Antonio F., Helthuis, Marinka, Jansen, John A., Jollie, Karel, Knapper, Steven, MacCabe, James H., Rujescu, Dan, Collier, David A., O'Donovan, Michael C, Owen, Michael J and Walters, James T.R. 2019. 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. Molecular Psychiatry 24 , pp. 328-337. 10.1038/s41380-018-0335-7

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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

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Springer Nature
ISSN: 1359-4184
Date of First Compliant Deposit: 14 December 2018
Date of Acceptance: 26 November 2018
Last Modified: 19 Oct 2019 03:54
URI: http://orca.cf.ac.uk/id/eprint/117670

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