To apply a comprehensive, unbiased systems-biology approach to explore the cellular specificity of known dystonia-related (DYT) genes, predict their functions, identify overlapping molecular pathways and test whether dystonia and neuropsychiatric disorders correlate genetically.

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. A large proportion of dystonia patients have an additional psychiatric condition, including anxiety, depression, obsessive-compulsive disorder and schizophrenia. Mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia. However, the physiological roles and the pathogenetic mechanisms of most DYT-genes are unknown.

To determine the cellular specificity of DYT-genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships amongst DYT-genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Finally, stratified linkage-disequilibrium regression score (s-LDSC) was used to test whether co-expression modules enriched for DYT-genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease.

The DYT-genes are significantly enriched in adult dopaminergic and striatal medium spiny neurons. Furthermore, the DYT-genes were enriched in 4 of the 220 gene co-expression modules tested. The identified modules derived from the substantia nigra, putamen, frontal cortex and white matter and were significantly enriched for genes associated with neuronal synaptic transmission. s-LDSC analysis showed significant enrichments of the heritability of depression, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules.

Multiple DYT-genes interact and contribute to the pathogenesis of dystonia likely through dysregulation of synaptic signalling in striatal and nigral dopaminergic neurons. Furthermore, given the enrichment of DYT-genes in co-expression modules also enriched for the heritability of psychiatric disorders, this suggests that psychiatric symptoms associated with dystonia are at least in part intrinsic to its pathophysiology.