Genetic Loci Analysis Of Schizophrenia And Clozapine Antipsychotic Leucopenia

Schizophrenia（schizophrenia,SCZ,MIM181500）is a relatively common mental disease,mainly manifested by disharmony in thinking,emotion and cognitive behavior disorder.Its prevalence in the world population,the incidence rate of about 1%.Antipsychotic drug therapy is the main treatment for schizophrenia,but most patients have poor prognosis or poor compliance.Several studies have shown that schizophrenia is a highly heritable polygenic disease,and hundreds of schizophrenia risk variants（including common single nucleotide polymorphisms and rare copy number variants）have been reported in the Genome-Wide Association Study（GWAS）.Through genome-wide association analysis and meta-analysis,Li et al.found new risk loci of 8p12.In order to further search for key risk genes related to the occurrence of schizophrenia in the coding region of 8p12,this study genotyped 2,403schizophrenia cases and 2,594 normal controls in the Han population,and found a total of148 single nucleotide polymorphisms,and passed the quality control for correlation analysis.Among them,the missense variant site rs201292574（NP＿006274.2:p.Ala211Thr）on TACC1 and the synonymous variant site rs45563241 on ADRB3 are nominally related to schizophrenia（rs201292574,P=0.033;rs45563241,P=0.039）.Both lost statistical significance after correction(P_FDR>0.05).Nevertheless,this study still provides data for exploring the genetic mechanism of schizophrenia and provides new experience for subsequent research.Clozapine is the only drug approved for the treatment of refractory schizophrenia.A key factor limiting its use is that it may cause serious adverse drug reactions.In this study,1,983 patients with schizophrenia treated with clozapine were genotyped.After quality control,it finally included 1,879 subjects（225 cases of leukopenia（white blood cell<4,000/L）43 cases of neutropenia（neutrophil<1,500/L）and 1,645 cases of controls）.Perform association analysis on common and rare SNP data.In addition,this study also refers to the genome-wide association analysis data of the European samples of Clozapine-induced Agranulocytosis Consortium（CIAC）.Subsequently,this study used the genome-wide variant annotation web tool to prioritize the selected variant sites and tested the transcriptional activity of the five priority variants with the highest scores using dual luciferase.This study discovered 9 new genome-wide positive correlation sites(P<5×10^-8),3new sites were related to leukopenia（rs377360,rs4773794,rs10512698）,and 6 were related to neutrophils Reduction of symptoms related（rs11698234,rs73482673,rs9808117,rs373695,rs7501702,rs8024434）.It contains 2 sites related to T cell-related genes（rs377360 and rs116982346）.In the cross-ancestral meta-analysis of European individuals and Han individuals,this study found a site close to the significance level of the whole genome(rs11753309,P=5.08×10^-8),which is in the major histocompatibility complex near the HLA-B gene in the body region.The dual luciferase report experiment showed that DNA fragments containing rs377360-T and rs4773794-G increased the transcriptional activity of HEK293 cells（P<0.01）,but were not observed in patients with clozapine-induced neutropenia sites that have a significant impact on transcriptional activity（P>0.05）.In conclusion,this study provides a new understanding of the genetic structure and biological etiology of schizophrenia.In summary,our findings on the genetic susceptibility of schizophrenia indicate that a large sample size is needed,and a more comprehensive study of coding region variants and regulatory variants is needed.The results of genome-wide association analysis and meta-analysis provide an opportunity for us to further understand the etiology of schizophrenia.Our research provides valuable insights into the genetic mechanism of clozapine in the treatment of schizophrenia-induced leukopenia and neutropenia,which can help improve the clinical management of clozapine-related schizophrenia treatment.In particular,the discovery of new genetic loci has laid a theoretical foundation for effective diagnosis and personalized treatment of schizophrenia.The discovery of new genetic markers has laid a theoretical foundation for effective diagnosis and personalized treatment of schizophrenia.