Publication Date

2014

Journal Title

Nat Commun

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 genomewide 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 x 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 x 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.

Volume Number

5

Pages

9

Document Type

Article

Status

Faculty

Facility

School of Medicine

Primary Department

Psychiatry

Additional Departments

Molecular Medicine

PMID

25187353

DOI

10.1038/ncomms5757


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Psychiatry Commons

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