Genome wide study of tardive dyskinesia in schizophrenia

Abstract

Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine mapping, we identified putative credible causal variants for three of the loci. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.

ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum

“…Although commonly observed in patients with schizophrenia, tardive dyskinesia can occur in individuals with other psychiatric disorders. Single-nucleotide polymorphisms in CALCOCO1 appear to confer threefold increase in tardive dyskinesia risk ( 489 ). Single-nucleotide polymorphisms in CALCOCO1 have also been associated with panic disorder, an anxiety disorder characterized by panic attacks and anticipatory anxiety ( 490 ).…”

Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

“…To investigate the genetic variability of the potential underlying mechanisms and pathways of TD, they applied a robust and thorough bioinformatic analysis, including meta-analysis, functional annotation, eQTLs, transcriptome-wide fine-mapping, polygenic risk score analyses and multivariate logistic regression analyses. The study revealed the importance of three genomic loci on chromosomes 1, 6 and 12 and a novel locus on chromosome 16, highlighting the importance of TNFRSF1B, EPB41L2, CALCOCO1 and GSE1 genes ( Lim et al, 2021 ). TNFRSF1B is a member of the tumor necrosis factor receptor superfamily and participates in the antiapoptotic signaling pathway.…”

“…TNFRSF1B is a member of the tumor necrosis factor receptor superfamily and participates in the antiapoptotic signaling pathway. It is expressed in immune cells, highlighting the importance of immune system in TD pathogenesis ( Lee and Kang 2011 ; Lanning et al, 2016 ; Lim et al, 2021 ). EPB41L2 is a membrane protein that was found to have a protective effect on motor activity.…”

“…EPB41L2 is a membrane protein that was found to have a protective effect on motor activity. Published data suggest that its deficiency in mice convoy motor movement dysfunctions due to its involvement in cytoskeletal binding ( Saitoh et al, 2017 ; Lim et al, 2021 ). CALCOCO1 was recently found to be involved in the autophagy of endoplasmic reticulum ( Nthiga et al, 2020 ) and the transcriptional activation of target genes in the Wnt/CTNNB1 pathway ( Mizuta et al, 2014 ).…”

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia

“…GRIN2B is located on chromosome 12p12 and codes for a polypeptide of 1484 amino acid residues, GluN2B or NR2B [ 25 ]. These genes have been investigated for possible involvement in the pathophysiology of TD in patients with schizophrenia, but the results of the studies are inconsistent [ 28 , 29 , 30 ].…”