-transparent.png){kind=logo}
Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. 2014
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
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.
Related Publications
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
April 2011,
The Journal of clinical psychiatry,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
April 2021,
Translational psychiatry,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
September 1994,
The Journal of clinical psychiatry,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
July 1998,
The international journal of neuropsychopharmacology,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
October 2011,
The American journal of psychiatry,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
April 1992,
Annals of internal medicine,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
January 2020,
PloS one,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
December 2003,
Tissue antigens,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
August 1995,
Blood,
Jacqueline I Goldstein, and
L Fredrik Jarskog, and
Chris Hilliard, and
Ana Alfirevic, and
Laramie Duncan, and
Denis Fourches, and
Hailiang Huang, and
Monkol Lek, and
Benjamin M Neale, and
Stephan Ripke, and
Kevin Shianna, and
Jin P Szatkiewicz, and
Alexander Tropsha, and
Edwin J C G van den Oord, and
Ingolf Cascorbi, and
Michael Dettling, and
Ephraim Gazit, and
Donald C Goff, and
Arthur L Holden, and
Deanna L Kelly, and
Anil K Malhotra, and
Jimmi Nielsen, and
Munir Pirmohamed, and
Dan Rujescu, and
Thomas Werge, and
Deborah L Levy, and
Richard C Josiassen, and
James L Kennedy, and
Jeffrey A Lieberman, and
Mark J Daly, and
Patrick F Sullivan
February 2015,
Acta dermato-venereologica,
