The genetics of drug-related movement disorders, an umbrella review of meta-analyses

Abstract

This umbrella review investigates which genetic factors are associated with drug-related movement disorders (DRMD), in an attempt to provide a synthesis of published evidence of candidate-gene studies. To identify all relevant meta-analyses, a literature search was performed. Titles and abstracts were screened by two authors and the methodological quality of included meta-analyses was assessed using 'the assessment of multiple systematic reviews' (AMSTAR) critical appraisal checklist. The search yielded 15 meta-analytic studies reporting on genetic variations in 10 genes. DRD3, DRD2, CYP2D6, HTR2A, COMT, HSPG2 and SOD2 genes have variants that may increase the odds of TD. However, these findings do not concur with early genome-wide association studies. Low-power samples are susceptible to 'winner's curse', which was supported by diminishing meta-analytic effects of several genetic variants over time. Furthermore, analyses pertaining to the same genetic variant were difficult to compare due to differences in patient populations, methods used and the choice of studies included in meta-analyses. In conclusion, DRMD is a complex phenotype with multiple genes that impact the probability of onset. More studies with larger samples using other methods than by candidate genes, are essential to developing methods that may predict the probability of DRMD. To achieve this, multiple research groups need to collaborate and a DRMD genetic database needs to be established in order to overcome winner's curse and publication bias, and to allow for stratification by patient characteristics. These endeavours may help the development of a test with clinical value in the prevention and treatment of DRMD.