Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study

Author:

Chen JianhuaORCID,Yang Ping,Zhang Qian,Chen RuiruiORCID,Wang Peng,Liu Benxiu,Sun Wensheng,Jian Xuemin,Xiang Siying,Zhou Juan,Li Ningning,Wang Ke,Gao Chengwen,Wen Yanqin,Wu Chuanhong,Zhang Jinmai,Zhao Yalin,Yang Qiangzhen,Li Meihang,Stewart RobertORCID,Sun Yuanchao,Pan Dun,Niu Yujuan,Wang ZhuoORCID,Xu YifengORCID,Li Xingwang,He LinORCID,Li ZhiqiangORCID,Shi YongyongORCID

Abstract

Abstract Background Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). Methods A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). Results The authors 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, and two T cell related genes (TRAC and TRAT1) were implicated. The authors 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. Conclusions The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

Funder

Shanghai Hospital Development Center

Science and Technology Commission of Shanghai Municipality

Taishan Scholar Foundation of Shandong Province

Natural Science Foundation of Shandong Province

Publisher

Springer Science and Business Media LLC

Subject

Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry and Mental health

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