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

Jacqueline I Goldstein; 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 Oord; 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

doi:10.1038/ncomms5757

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

Jacqueline I Goldstein, 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 Oord, Ingolf Cascorbi, Michael Dettling, Ephraim Gazit, Donald C Goff, Arthur L Holden, Deanna L KellyAnil 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

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	4757
Journal	Nature Communications
Volume	5
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms5757
Publication status	Published - 2014

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Goldstein, J. I., Fredrik Jarskog, L., Hilliard, C., Alfirevic, A., Duncan, L., Fourches, D., Huang, H., Lek, M., Neale, B. M., Ripke, S., Shianna, K., Szatkiewicz, J. P., Tropsha, A., van den Oord, E. J., Cascorbi, I., Dettling, M., Gazit, E., Goff, D. C., Holden, A. L., ... Sullivan, P. F. (2014). Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nature Communications, 5, Article 4757. https://doi.org/10.1038/ncomms5757

@article{65ae464d8f1d48bfad8fb2e206370db2,

title = "Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles",

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.",

author = "Goldstein, {Jacqueline I} and {Fredrik Jarskog}, L and Chris Hilliard and Ana Alfirevic and Laramie Duncan and Denis Fourches and Hailiang Huang and Monkol Lek and Neale, {Benjamin M} and Stephan Ripke and Kevin Shianna and Szatkiewicz, {Jin P} and Alexander Tropsha and {van den Oord}, {Edwin Jcg} and Ingolf Cascorbi and Michael Dettling and Ephraim Gazit and Goff, {Donald C} and Holden, {Arthur L} and Kelly, {Deanna L} and Malhotra, {Anil K} and Jimmi Nielsen and Munir Pirmohamed and Dan Rujescu and Thomas Werge and Levy, {Deborah L} and Josiassen, {Richard C} and Kennedy, {James L} and Lieberman, {Jeffrey A} and Daly, {Mark J} and Sullivan, {Patrick F}",

year = "2014",

doi = "10.1038/ncomms5757",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Goldstein, JI, Fredrik Jarskog, L, Hilliard, C, Alfirevic, A, Duncan, L, Fourches, D, Huang, H, Lek, M, Neale, BM, Ripke, S, Shianna, K, Szatkiewicz, JP, Tropsha, A, van den Oord, EJ, Cascorbi, I, Dettling, M, Gazit, E, Goff, DC, Holden, AL, Kelly, DL, Malhotra, AK, Nielsen, J, Pirmohamed, M, Rujescu, D, Werge, T, Levy, DL, Josiassen, RC, Kennedy, JL, Lieberman, JA, Daly, MJ & Sullivan, PF 2014, 'Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles', Nature Communications, vol. 5, 4757. https://doi.org/10.1038/ncomms5757

TY - JOUR

T1 - Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles

AU - Goldstein, Jacqueline I

AU - Fredrik Jarskog, L

AU - Hilliard, Chris

AU - Alfirevic, Ana

AU - Duncan, Laramie

AU - Fourches, Denis

AU - Huang, Hailiang

AU - Lek, Monkol

AU - Neale, Benjamin M

AU - Ripke, Stephan

AU - Shianna, Kevin

AU - Szatkiewicz, Jin P

AU - Tropsha, Alexander

AU - van den Oord, Edwin Jcg

AU - Cascorbi, Ingolf

AU - Dettling, Michael

AU - Gazit, Ephraim

AU - Goff, Donald C

AU - Holden, Arthur L

AU - Kelly, Deanna L

AU - Malhotra, Anil K

AU - Nielsen, Jimmi

AU - Pirmohamed, Munir

AU - Rujescu, Dan

AU - Werge, Thomas

AU - Levy, Deborah L

AU - Josiassen, Richard C

AU - Kennedy, James L

AU - Lieberman, Jeffrey A

AU - Daly, Mark J

AU - Sullivan, Patrick F

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms5757

DO - 10.1038/ncomms5757

M3 - Journal article

C2 - 25187353

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4757

ER -

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

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