Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders

Abstract

Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in patients with dystonia. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated 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 among dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, 4 of 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrate significant enrichments of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules, and a significant enrichment of the heritability of Parkinson’s disease within the substantia nigra module. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia

“…The potential therapeutic relevance of this path is highlighted by cases demonstrating the efficacy of deep brain stimulation of cerebellar outflow regions in patients with secondary dystonias, 32‐35 with whom a dysfunctional network involving cerebellar outflow pathways is shared by patients with CD 31 . Similar DTI abnormalities (decrease of FA and AD) are also found in conditions characterized by disrupted brain maturation, 36‐40 which is supported by the association of the idiopathic dystonia spectrum with neurodevelopmental disorders, such as major depressive disorder, schizophrenia, and obsessive‐compulsive disorder 41,42 …”

Neurology and Psychiatry Get Closer Again: Lessons From Dystonia

“…Moreover, because this approach can be utilized only with recognized genes, novel genetic discoveries will possibly detect functional convergence in other brain regions relevant to dystonia (ie, cerebellum). Finally, this work 2 highlights shared biological contributions to dystonia and psychiatric disorders. If, on the one hand, it supports the need to transform the current model of care of dystonia into a multidisciplinary model, 1 on the other hand, it would raise the alternative argument of dystonia representing a downstream clinical manifestation of a primary psychiatric disorder.…”

“…In their recent work, 2 Mencacci and colleagues applied a comprehensive system biology approach primarily using transcriptome analyses to explore (1) which brain cells are most relevant to several genes causing prominent dystonia without structural or degenerative abnormalities and including those associated with different phenotypes of isolated, associated, and paroxysmal dystonia; (2) whether these genes converge toward shared cellular pathways; and (3) if a common genetic architecture between monogenic dystonia and psychiatric disorders exists.…”

Dystonia updates: definition, nomenclature, clinical classification, and etiology

“…Even more complex systems biology approaches may lead to the development of further means of categorization of dystonia patients. A recent study has modeled the contribution of dystonia-associated genes to dystonia pathology (Mencacci et al 2020 ). This study also highlights that both types of studies, candidate-based genetic and functional studies as well as hypothesis-free studies, will likely contribute to a more refined subgrouping of the dystonias in the future.…”