title: Genome-wide association study of lymphoblast cell viability after clozapine exposure.
abstract: Clozapine is an antipsychotic drug with proven efficacy in treatment-resistant schizophrenia but also known to induce potentially lethal agranulocytosis (CIA) in 1% of patients. Genetic factors are likely to play a role in the molecular basis of CIA. We explored an in vitro system to study the genetic susceptibility of CIA. Cell viability was measured in 90 lymphoblast cell lines exposed to a series of increasing concentrations of clozapine for 48 hr. Quantitative trait measures of cell viability as well as area under the survival curve were used in a linear mixed model for genome-wide association analyses. The estimated heritability of clozapine-induced cell viability reduction in these cell lines is h2=0.76. No genome-wide significant association was observed after correction for multiple testing. Two independent loci with nominal evidence of association were observed at 30× clinical clozapine concentration: rs2709505 (P=1.41×10(-8)) in an intron of MDFIC and rs10457252 (P=1.79×10(-8)) located in a gene desert at chromosome 6q21. We identified one locus (rs1293970) near PRG4 that was consistently associated for all separate concentration analyses at P<5×10(-5). PRG4 encodes hemangiopoietin, a growth stimulator for hematopoietic stem cells. No evidence was observed for involvement of the MHC region. Our results demonstrate that clozapine-induced viability reduction in lymphoblast cell lines is a heritable, polygenic trait. Thus, in vitro models of CIA might be a useful tool for future discovery of genetic risk factors, although larger sample sizes will be required to unambiguously identify these loci.
authors: UCLA Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, California; Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, The Netherlands.
authors: S A J
authors: SA
authors: de With
authors: S L
authors: SL
authors: Pulit
authors: T
authors: T
authors: Wang
authors: W G
authors: WG
authors: Staal
authors: W W
authors: WW
authors: van Solinge
authors: P I W
authors: PI
authors: de Bakker
authors: R A
authors: RA
authors: Ophoff
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D055106:Genome-Wide Association Study; D006801:Humans; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008285:Major Histocompatibility Complex / Q000235:genetics; D019655:Quantitative Trait, Heritable
chemical_list: D003024:Clozapine
keywords: Genome-wide association study; agranulocytosis; cell viability; clozapine; clozapine-induced agranulocytosis; lymphoblasts