DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Clozapine-induced agranulocytosis. The EFO term drug-induced agranulocytosis, response to clozapine was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: drug-induced agranulocytosis, response to clozapine

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

JI Goldstein, LF Jarskog, C Hilliard, A Alfirevic, L Duncan, D Fourches, H Huang, M Lek, BM Neale, S Ripke, K Shianna, JP Szatkiewicz, A Tropsha, EJ van den Oord, I Cascorbi, M Dettling, E Gazit, DC Goff, AL Holden, DL Kelly, AK Malhotra, J Nielsen, M Pirmohamed, D Rujescu, T Werge, DL Levy, RC Josiassen, JL Kennedy, JA Lieberman, MJ Daly, PF Sullivan

TITLE:

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

JOURNAL:

Nature communications Sep 2014, Vol 5, pp. 4757

ABSTRACT:

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG. PUBMED: 25187353
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