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

• DOI: 10.1038/ncomms5757
• Publication Date: 2014-09-04T14:19:45Z
• Authors: Jacqueline I. Gol...; L. Fredrik Jarskog; Chris Hilliard; Ana Alfirevic; Laramie Duncan; Denis Fourches; Hailiang Huang; Monkol Lek; Benjamin M. Neale; Stephan Ripke; Kevin Shianna; Jin P. Szatkiewicz; Alexander Tropsha; Edwin JCG van den...; Ingolf Cascorbi; Michael Dettling; Ephraim Gazit; Donald C. Goff; Arthur L. Holden; Deanna L. Kelly; Anil K. Malhotra; Jimmi Nielsen; Munir Pirmohamed; Dan Rujescu; Thomas Werge; Deborah L. Levy; Richard C. Josiassen; James L. Kennedy; Jeffrey A. Lieberman; Mark J. Daly; Patrick F. Sullivan
• Keywords: 0301 basic medicine; Heterozygote; 610; Severity of Illness Index; Article; 3. Good health; 03 medical and health sciences; Amino Acid Substitution; Gene Frequency; Psychotic Disorders; HLA-B Antigens; Case-Control Studies; 616; Odds Ratio; HLA-DQ beta-Chains; Humans; Exome; Genetic Predisposition to Disease; Clozapine; Alleles; Agranulocytosis; Antipsychotic Agents; Genome-Wide Association Study

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% 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.