Background:Antipsychotic-induced movement disorders(AIMDs)are prevalent side effects of antipsychotics,particularly during the acute phase of treatment.This study aimed to elucidate the genetic mechanisms underlying A...Background:Antipsychotic-induced movement disorders(AIMDs)are prevalent side effects of antipsychotics,particularly during the acute phase of treatment.This study aimed to elucidate the genetic mechanisms underlying AIMDs using a genome-wide association study(GWAS).Methods:GWASs on AIMDs were conducted in three independent cohorts:a discovery cohort of 3067 patients(2016 subjects were reserved after quality control),a validation cohort of 277 patients,and a multi-ancestry validation cohort of 766 patients.Subsequent post-GWAS analyses included gene-based analyses,transcriptome-wide association studies(TWASs),and polygenic risk score(PRS)profiling.Results:Our study identified two loci located in RAB44 gene(rs116249243,P=5.98×10^(-9);rs117097482,P=1.17×10^(-8))associated with extrapyramidal symptoms(EPSs),1 locus(rs6826172,P=5.56×10^(-9))related to akathisia,and 76 loci linked to involuntary movements(11 genes were mapped).Risk loci located in CNTNAP2,LUZP2,TMEM167A,and RAB44 genes were successfully replicated in the validation cohort,whereas the locus located in RAB44 was also replicated in the multi-ancestry cohort.Gene-based analyses indicated that XRCC4 and PAIP2B reached significance at the genome-wide level in involuntary movements.Tissue expression analysis revealed that involuntary movement-related genes are predominantly expressed in the substantia nigra.Additionally,the TWAS suggested a causal relationship between XRCC4 and involuntary movement.The PRSs derived from the discovery cohort significantly predicted AIMDs in the validation cohort,with area under the receiver operating characteristic curve(AUC)values from 0.60 to 0.80.Conclusions:Our findings highlight the role of substantia nigra related gene polymorphisms in AIMDs.This study provides novel insights into the pathogenesis of AIMDs and supports the potential for personalized treatment approaches for schizophrenia.展开更多
BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS) is currently used for the treatment of complications of portal hypertension. The incidence of hepatic encephalopathy(HE) remains a problem in TIPS placeme...BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS) is currently used for the treatment of complications of portal hypertension. The incidence of hepatic encephalopathy(HE) remains a problem in TIPS placement. It has been reported that the right branch mainly receives superior mesenteric venous blood while the left branch mainly receives blood from the splenic vein. We hypothesized that targeted puncture of the left portal vein would divert the non-nutritive blood from the splenic vein into the TIPS shunt; therefore, targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE.AIM To evaluate the influence of targeted puncture of left branch of portal vein in TIPS on HE.METHODS A retrospective analysis of 1244 patients with portal-hypertension-related complications of refractory ascites or variceal bleeding who underwent TIPS from January 2000 to January 2013 was performed. Patients were divided into group A(targeting left branch of portal vein, n = 937) and group B(targeting right branch of portal vein, n = 307). TIPS-related HE and clinical outcomes were analyzed.RESULTS The symptoms of ascites and variceal bleeding disappeared within a short time.By the endpoint of follow-up, recurrent bleeding and ascites did not differ significantly between groups A and B(P = 0.278, P = 0.561, respectively).Incidence of HE differed significantly between groups A and B at 1 mo(14.94% vs36.80%, χ~2 = 4.839, P = 0.028), 3 mo(12.48% vs 34.20%, χ~2 = 5.054, P = 0.025), 6 mo(10.03% vs 32.24%, χ~2 = 6.560, P = 0.010), 9 mo(9.17% vs 31.27%, χ~2 = 5.357, P =0.021), and 12 mo(8.21% vs 28.01, χ~2 = 3.848, P = 0.051). There were no significant differences between groups A and B at 3 years(6.61% vs 7.16%, χ~2 = 1.204, P =0.272) and 5 years(5.01% vs 6.18%, χ~2 = 0.072, P = 0.562). The total survival rate did not differ between groups A and B(χ~2 = 0.226, P = 0.634, log-rank test).CONCLUSION Targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE but has no direct influence on prognosis of portalhypertension-related complications.展开更多
基金supported by the National Natural Science Foundation of China(82330042,82441005 and 82301687)the National Key R&D Program of China(2023YFE0119400)+9 种基金the Capital’s Funds for Health Improvement and Research(2024-1-4111)the STI2030-Major Projects-2021ZD0200702Fundamental Research Funds for the Central Universities(Peking University Medicine Fund for world’s leading discipline or discipline cluster development,BMU2022DJXK007)the Beijing Municipal Health Commission Research Ward Programme(3rd batch)Beijing Nova Program(20230484425)the Beijing Municipal Science&Technology Commission,Administrative Commission of Zhongguancun Science Park(Z221100003522010)the China Postdoctoral Science Foundation(2024M760141 and 2022M720302)the National Postdoctoral Program for Innovative Talents(BX20240029)the Beijing Natural Science Foundation(7254462)the Peking University Medicine Sailing Program for Young Scholars’Scientific&Technological Innovation,the Fundamental Research Funds for the Central Universities(BMU2025YFJHPY044 and BMU2025YFJHPY046).
文摘Background:Antipsychotic-induced movement disorders(AIMDs)are prevalent side effects of antipsychotics,particularly during the acute phase of treatment.This study aimed to elucidate the genetic mechanisms underlying AIMDs using a genome-wide association study(GWAS).Methods:GWASs on AIMDs were conducted in three independent cohorts:a discovery cohort of 3067 patients(2016 subjects were reserved after quality control),a validation cohort of 277 patients,and a multi-ancestry validation cohort of 766 patients.Subsequent post-GWAS analyses included gene-based analyses,transcriptome-wide association studies(TWASs),and polygenic risk score(PRS)profiling.Results:Our study identified two loci located in RAB44 gene(rs116249243,P=5.98×10^(-9);rs117097482,P=1.17×10^(-8))associated with extrapyramidal symptoms(EPSs),1 locus(rs6826172,P=5.56×10^(-9))related to akathisia,and 76 loci linked to involuntary movements(11 genes were mapped).Risk loci located in CNTNAP2,LUZP2,TMEM167A,and RAB44 genes were successfully replicated in the validation cohort,whereas the locus located in RAB44 was also replicated in the multi-ancestry cohort.Gene-based analyses indicated that XRCC4 and PAIP2B reached significance at the genome-wide level in involuntary movements.Tissue expression analysis revealed that involuntary movement-related genes are predominantly expressed in the substantia nigra.Additionally,the TWAS suggested a causal relationship between XRCC4 and involuntary movement.The PRSs derived from the discovery cohort significantly predicted AIMDs in the validation cohort,with area under the receiver operating characteristic curve(AUC)values from 0.60 to 0.80.Conclusions:Our findings highlight the role of substantia nigra related gene polymorphisms in AIMDs.This study provides novel insights into the pathogenesis of AIMDs and supports the potential for personalized treatment approaches for schizophrenia.
文摘BACKGROUND Transjugular intrahepatic portosystemic shunt(TIPS) is currently used for the treatment of complications of portal hypertension. The incidence of hepatic encephalopathy(HE) remains a problem in TIPS placement. It has been reported that the right branch mainly receives superior mesenteric venous blood while the left branch mainly receives blood from the splenic vein. We hypothesized that targeted puncture of the left portal vein would divert the non-nutritive blood from the splenic vein into the TIPS shunt; therefore, targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE.AIM To evaluate the influence of targeted puncture of left branch of portal vein in TIPS on HE.METHODS A retrospective analysis of 1244 patients with portal-hypertension-related complications of refractory ascites or variceal bleeding who underwent TIPS from January 2000 to January 2013 was performed. Patients were divided into group A(targeting left branch of portal vein, n = 937) and group B(targeting right branch of portal vein, n = 307). TIPS-related HE and clinical outcomes were analyzed.RESULTS The symptoms of ascites and variceal bleeding disappeared within a short time.By the endpoint of follow-up, recurrent bleeding and ascites did not differ significantly between groups A and B(P = 0.278, P = 0.561, respectively).Incidence of HE differed significantly between groups A and B at 1 mo(14.94% vs36.80%, χ~2 = 4.839, P = 0.028), 3 mo(12.48% vs 34.20%, χ~2 = 5.054, P = 0.025), 6 mo(10.03% vs 32.24%, χ~2 = 6.560, P = 0.010), 9 mo(9.17% vs 31.27%, χ~2 = 5.357, P =0.021), and 12 mo(8.21% vs 28.01, χ~2 = 3.848, P = 0.051). There were no significant differences between groups A and B at 3 years(6.61% vs 7.16%, χ~2 = 1.204, P =0.272) and 5 years(5.01% vs 6.18%, χ~2 = 0.072, P = 0.562). The total survival rate did not differ between groups A and B(χ~2 = 0.226, P = 0.634, log-rank test).CONCLUSION Targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE but has no direct influence on prognosis of portalhypertension-related complications.
