Genetic Risk of Clozapine Induced Leukopenia and Neutropenia: A Genome-Wide Association Study

Abstract

Background: Antipsychotics can improve psychotic symptoms, but treatment responses vary widely. Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is also associated with several adverse effects such as metabolic syndrome and leukopenia. The mechanism of clozapine induced leukopenia (CIL) has not yet been fully elucidated. Genetic factors are likely to play an important role in the molecular basis, but most investigations have focused on individuals of European ancestry. In this manuscript, we report the first genome-wide association study (GWAS) of CIL and clozapine induced neutropenia (CIN) in a Chinese population. Methods: We performed a GWAS in up to 1,879 patients (225 CIL cases with WBC < 4,000 mm−3, including 43 CIN cases with ANC < 1500 mm−3, and 1654 controls) of Chinese descent. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. We also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine Induced Agranulocytosis Consortium (CIAC). Findings: We identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10−8). Three novel loci were associated with CIL while six were associated with CIN. We identified two T cell related genes in this study (TRAC and TRAT1). We also observed that one locus with evidence close to genome-wide significance (P = 5·08 × 10−8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. Interpretation: Our results provide novel understanding of potential genetic and immune mechanisms for CIL and CIN. Funding Statement: This work was supported by the National Key RD Shanghai Youth Top-notch Talent Support Program to J.C., Shanghai Mental Health Center (2016-fx-02), Shanghai Municipal Commission of Science and Technology (17JC1402900, 17490712200, 18DZ2260200), Shanghai Municipal Health Commission (ZK2015B01, 201540114), Scientific Research and Development Fund of Shanghai Jiao Tong University (19X150010012), Shanghai Municipal Science and Technology Major Project (2018SHZDZX05), Innovative Research Team of High-Level Local Universities in Shanghai and Shanghai Clinical Research Center for Mental Health (19MC1911100). R.S. is part-funded by: i) the National Institute for Health Research (NIHR) Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King’s College London; ii) a Medical Research Council (MRC) Mental Health Data Pathfinder Award to King’s College London; iii) an NIHR Senior Investigator Award; iv) the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust. Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: In accordance with the principles in Declaration of Helsinki, the study was approved by the Ethics Committee at the Bio-X Institutes of Shanghai Jiao Tong University and the written informed consent was obtained from each participant. It is confirmed that the research complied with the Guidance of the Ministry of Science and Technology (MOST) for the Review and Approval of Human Genetic Resources.