scholarly journals Genome wide study of tardive dyskinesia in schizophrenia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Keane Lim ◽  
Max Lam ◽  
Clement Zai ◽  
Jenny Tay ◽  
Nina Karlsson ◽  
...  
Keyword(s):  
Tardive Dyskinesia ◽  
Age Of Onset ◽  
Involuntary Movement ◽  
Fold Increase ◽  
Severe Condition ◽  
Duration Of Illness ◽  
Genome Wide ◽  
Causal Variants ◽  
Post Hoc ◽  
Genome Wide Study

AbstractTardive 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.

scholarly journals Genome Wide Study of Tardive Dyskinesia in Schizophrenia

2018 ◽  
Author(s):  
Max Lam ◽  
Keane Lim ◽  
Jenny Tay ◽  
Nina Karlsson ◽  
Smita N Deshpande ◽  
...  
Keyword(s):  
Tardive Dyskinesia ◽  
Genetic Architecture ◽  
Multivariate Analyses ◽  
Involuntary Movement ◽  
Biological Pathways ◽  
Severe Condition ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Causal Variants ◽  
Genome Wide Study

AbstractTardive 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. Multivariate analyses of polygenic risk for TD supports the genetic susceptibility of TD, with relatively lower allele frequencies variants being associated with TD, beyond that of antipsychotic medication. Together, these findings provide new insights into the genetic architecture and biology of TD.

scholarly journals Deutetrabenazine Reduces Severe Tardive Dyskinesia Movements in a 3-year Open-Label Extension Trial

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 156-156
Author(s):  
Nayla Chaijale ◽  
Joseph Bona ◽  
Hadas Barkay ◽  
Amanda Wilhelm ◽  
Mark Forrest Gordon
Keyword(s):  
Tardive Dyskinesia ◽  
Treatment Guidelines ◽  
Involuntary Movement ◽  
Open Label ◽  
Percent Change ◽  
Open Label Extension ◽  
Pharmaceutical Industries ◽  
Clinically Significant ◽  
Post Hoc ◽  
Lost To Follow Up

AbstractBackgroundThere are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements.MethodsSubgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline.Results337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was –11.0±0.8 versus –5.1±0.3; percent change from baseline was –60.1%±3.6% versus –55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%).ConclusionsPatients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

scholarly journals Using Item 8 of the Abnormal Involuntary Movement Scale (AIMS) to Assess Improvement in Patients with Tardive Dyskinesia

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 152-152
Author(s):  
Leslie Citrome ◽  
Leslie Lundt ◽  
Chirag Shah ◽  
Tara Carmack
Keyword(s):  
Tardive Dyskinesia ◽  
Involuntary Movement ◽  
Real Life ◽  
Meaningful Improvement ◽  
Once Daily ◽  
Abnormal Involuntary Movement Scale ◽  
Clinical Measure ◽  
Long Term Study ◽  
Using Data ◽  
Post Hoc

AbstractObjectiveThe Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) is usually the primary efficacy measure in tardive dyskinesia (TD) clinical trials. However, item 8 of the AIMS (clinician’s global impression of severity) might also be an appropriate assessment in real-life healthcare settings. To explore the potential of item 8 as a clinical measure, post hoc analyses were conducted using data from a long-term study of valbenazine, an approved TD medication.MethodsIn KINECT 4 (NCT02405091), adults with TD received once-daily valbenazine (40 or 80 mg) for 48 weeks. Analyses included two sets of AIMS item 8 scores: based on investigators ratings of item 8 using protocol-defined descriptors; and based on investigators highest scores from items 1–7 (analyzed post hoc). Shift analyses included an improvement from score =3 at baseline (moderate or severe) to score =2 at Week 48 (none to mild).ResultsAt baseline in all participants (N=163), AIMS item 8 mean scores were 3.2 (protocol) and 3.3 (post hoc). In participants with a score =3 at baseline per investigators ratings using protocol-defined descriptors, 95.9% [94/98] shifted to a score =2 by Week 48. A similar result (93.9% [93/99]) was found when item 8 was based on investigators highest scores from items 1–7.ConclusionShift analyses using AIMS item 8 scores indicated that most participants in KINECT 4 had a clinically meaningful improvement after 48 weeks of once-daily treatment with valbenazine. AIMS item 8 may be an appropriate clinical measure for assessing changes in TD severity.FundingNeurocrine Biosciences, Inc.

scholarly journals Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shuquan Rao ◽  
Yao Yao ◽  
Daniel E. Bauer
Keyword(s):  
Genome Editing ◽  
Genetic Variants ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Functional Studies ◽  
Functional Genetics ◽  
Genome Wide ◽  
Causal Variants ◽  
Experimental Approaches

AbstractGenome-wide association studies (GWAS) have uncovered thousands of genetic variants that influence risk for human diseases and traits. Yet understanding the mechanisms by which these genetic variants, mainly noncoding, have an impact on associated diseases and traits remains a significant hurdle. In this review, we discuss emerging experimental approaches that are being applied for functional studies of causal variants and translational advances from GWAS findings to disease prevention and treatment. We highlight the use of genome editing technologies in GWAS functional studies to modify genomic sequences, with proof-of-principle examples. We discuss the challenges in interrogating causal variants, points for consideration in experimental design and interpretation of GWAS locus mechanisms, and the potential for novel therapeutic opportunities. With the accumulation of knowledge of functional genetics, therapeutic genome editing based on GWAS discoveries will become increasingly feasible.

Visual Cortex Alterations in Early and Late Blind Subjects During Tactile Perception

Perception ◽  
2021 ◽  
Vol 50 (3) ◽  
pp. 249-265
Author(s):  
A. Ankeeta ◽  
S. Senthil Kumaran ◽  
Rohit Saxena ◽  
Sada N. Dwivedi ◽  
Naranamangalam R. Jagannathan
Keyword(s):  
Visual Cortex ◽  
Children And Adolescents ◽  
Age Of Onset ◽  
Human Subjects ◽  
Functional Results ◽  
Blood Oxygen Level Dependent ◽  
Tactile Perception ◽  
Blood Oxygen Level ◽  
Sensory Motor ◽  
Post Hoc

Involvement of visual cortex varies during tactile perception tasks in early blind (EB) and late blind (LB) human subjects. This study explored differences in sensory motor networks associated with tactile task in EB and LB subjects and between children and adolescents. A total of 40 EB subjects, 40 LB subjects, and 30 sighted controls were recruited in two subgroups: children (6–12 years) and adolescents (13–19 years). Data were acquired using a 3T MR scanner. Analyses of blood oxygen level dependent (BOLD), functional connectivity (FC), correlation, and post hoc test for multiple comparisons were carried out. Difference in BOLD activity was observed in EB and LB groups in visual cortex during tactile perception, with increased FC of visual with dorsal attention and sensory motor networks in EB. EB adolescents exhibited increased connectivity with default mode and salience networks when compared with LB. Functional results correlated with duration of training, suggestive of better performance in EB. Alteration in sensory and visual networks in EB and LB correlated with duration of tactile training. Age of onset of blindness has an effect in cross-modal reorganization of visual cortex in EB and multimodal in LB in children and adolescents.

scholarly journals Genome-wide fine-mapping identifies pleiotropic and functional variants that predict many traits across global cattle populations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ruidong Xiang ◽  
Iona M. MacLeod ◽  
Hans D. Daetwyler ◽  
Gerben de Jong ◽  
Erin O’Connor ◽  
...  
Keyword(s):  
Dairy Cattle ◽  
Chromosome Segment ◽  
Multiple Traits ◽  
Functional Variants ◽  
Genome Wide ◽  
The Usa ◽  
Pleiotropic Qtl ◽  
Causal Variants ◽  
Genetic Value ◽  
Bayesian Mixture Models

AbstractThe difficulty in finding causative mutations has hampered their use in genomic prediction. Here, we present a methodology to fine-map potentially causal variants genome-wide by integrating the functional, evolutionary and pleiotropic information of variants using GWAS, variant clustering and Bayesian mixture models. Our analysis of 17 million sequence variants in 44,000+ Australian dairy cattle for 34 traits suggests, on average, one pleiotropic QTL existing in each 50 kb chromosome-segment. We selected a set of 80k variants representing potentially causal variants within each chromosome segment to develop a bovine XT-50K genotyping array. The custom array contains many pleiotropic variants with biological functions, including splicing QTLs and variants at conserved sites across 100 vertebrate species. This biology-informed custom array outperformed the standard array in predicting genetic value of multiple traits across populations in independent datasets of 90,000+ dairy cattle from the USA, Australia and New Zealand.

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