Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia

Abstract

Background and objectives:Dystonia is a genetically complex disease with both monogenic and polygenic causes. For the latter, numerous genetic associations studies have been performed with largely inconsistent results. The aim of this study was to perform a field synopsis including systematic meta-analyses of genetic association studies in isolated dystonia Methods: For the field synopsis we systematically screened and scrutinized the published literature using NCBI's PubMed database. For genetic variants with sufficient information in at least two independent datasets, random-effects meta-analyses were performed, including meta-analyses stratified by ethnic descent and dystonia subtypes.Results: A total of 3,575 articles were identified and scrutinized resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While our meta-analyses pinpointed several significant association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data. Conclusions:Our study provides an up-to-date summary of the status of dystonia genetic association studies. Additional large-scale studies are needed to better understand the genetic causes of isolated dystonia.

Linking Penetrance and Transcription in DYT‐THAP1: Insights From a Human iPSC‐Derived Cortical Model

“…29 Dopamine receptor genes, including DRD1, DRD2, and DRD3, have been tested repeatedly for genetic associations with (idiopathic) dystonia, and at least one single-nucleotide variant in DRD1 might increase the risk to develop dystonia. 30 Alteration of striatal dopaminergic neurotransmission was found in a knockout mouse model of myoclonus dystonia, which is another form of combined dystonia. 31 Our data now suggest that DRD4 expression levels might play a role in mediating reduced penetrance in THAP1 mutation carriers.…”

“…Further, using a KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis in a conditional knockout mouse model, dopaminergic synaptic signaling was among the top hits, triggered mainly by DRD2 dysregulation 29 . Dopamine receptor genes, including DRD1 , DRD2 , and DRD3 , have been tested repeatedly for genetic associations with (idiopathic) dystonia, and at least one single‐nucleotide variant in DRD1 might increase the risk to develop dystonia 30 . Alteration of striatal dopaminergic neurotransmission was found in a knockout mouse model of myoclonus dystonia, which is another form of combined dystonia 31 .…”

Monogenic Causes of Dystonic Syndromes: Common in Dystonic Cerebral Palsy, Rare in Isolated Dystonia

“…One should also consider the possibility of dystonia as a polygenic disorder with pathogenic variants or genetic risk factors in several genes jointly underlying disease susceptibility. To this end, available data are still very limited, calling for additional genome‐wide association studies with larger sample sizes 5 . Although brain tissue is largely inaccessible in living dystonia patients, another interesting aspect regarding disease etiology will be epigenetics.…”

“…To this end, available data are still very limited, calling for additional genome-wide association studies with larger sample sizes. 5 Although brain tissue is largely inaccessible in living dystonia patients, another interesting aspect regarding disease etiology will be epigenetics.…”