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 US 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=4.21x10 -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=3.44x10 -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.

Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism

“…In order to select a sample of individuals with homogeneous genetic ancestry, we selected a custom panel of ancestry informative markers (AIMs), as described previously (38). Briefly, using principal components and a classification algorithm based on linear discriminant analysis, we identified 5,900 CLOZUK2 individuals with >90% probability of European ancestry.…”

How well do we understand the basis of classic selective sweeps in humans?

“…rs3827760 in EDAR has been associated with a range of hair , chin and ear shape phenotypes. In other cases, associations can be more difficult to interpret: for example ACKR1 rs2814778 is associated with lower numbers of neutrophils , or LCT rs4988235 with increased BMI . These associations, given our extensive understanding of these variants and their selective histories, are likely to reflect indirect or pleiotropic effects of the variant.…”

“…neutrophils [140], or LCT rs4988235 with increased BMI [141]. These associations, given our extensive understanding of these variants and their selective histories, are likely to reflect indirect or pleiotropic effects of the variant.…”

Evaluating the promise of inclusion of African ancestry populations in genomics

“…47 The first GWAS of neutrophil counts during clozapine treatment (for schizophrenia) conducted in individuals of African ancestry identified a key role for the well-known African ancestry-specific Duffy allele in risk of neutropenia upon treatment, thereby improving our understanding of the differential rates of discontinuation of clozapine by ethnicity. 49 Major warfarin-associated bleeding occurs more commonly among those with African ancestry, though genetic risk factors associated with this serious outcome had not been well-studied in these individuals. A recent case-control study among individuals of African ancestry 50 was able to identify a locus that associated with more than eight times greater risk of major warfarin-associated bleeding.…”