Association between Tardive Dyskinesia and Dopamine Receptor Genes among Patients with Chronic Schizophrenia Public Deposited

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  • March 20, 2019
  • Tsai, Huei-Ting
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • This dissertation aims to study associations between genetic variants and prevalent tardive dyskinesia (TD) among patients with chronic schizophrenia. The etiology of TD is largely unknown but dopamine receptors (DR) have been proposed as the drug target of anti-schizophrenic effects. In addition, the blockade of the dopaminergic pathway from long-term antipsychotic use likely influences the etiology of TD. Therefore, this study interrogated the relationship between DR genes (DRD 1, 2, 3, 4 and 5) and the prevalence of TD. The first study conducted as part of this dissertation was a meta-analysis of 13 association studies between DRD3 rs6280 and prevalent TD. Results from the meta-analysis implied strong publication bias in the studies on the relationship between rs6280 and TD. Study characteristics moderately associated with heterogeneous effect estimates in the published literature include publication year, criteria of subject's enrollment, TD assessment and diagnosis, age, percent female, and ancestry. In contrast, the summary estimate obtained when assuming a recessive mode of inheritance was not vulnerable to publication bias or heterogeneity in the published literature and indicated no association between rs6280 and TD (POR= 0.93, 95% C.I.= 0.70, 1.23). The second study from this dissertation was a cohort study about associations between TD susceptibility and 54 single nucleotide polymorphisms (SNPs) in all DR genes. Study subjects were 711 participants with chronic schizophrenia in the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study. Two hundred and seven participants who ever met the Schooler-Kane criteria in any one of Abnormal Involuntary Movement Scale (AIMS) evaluations in the CATIE were defined as TD. Several DRD1-3 SNPs demonstrated statistically significant associations with TD. However, after multiple comparison adjustments, no SNPs or haplotypes in DR genes displayed statistically significant association with TD. In summary, results from a comprehensive meta-analysis of 13 genetic association studies demonstrated no association between polymorphisms of rs6280 and TD. In addition, no association was detected in a cohort study interrogating the relationship between 54 SNPs in DR genes and TD among 711 CATIE participants. These findings suggest that SNPs in DR genes do not exert a strong effect on the pathophysiology of TD.
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  • North, Kari
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