Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders
Authors: Mencacci Niccolò E , Reynolds Regina H , Ruiz Sonia Garcia , Vandrovcova Jana , Forabosco Paola , Sánchez-Ferrer Alvaro , Volpato Viola ,   UK Brain Expression Consortium, Botía Juan A , D'Sa Karishma , Forabosco Paola , Guelfi Sebastian , Hardy John , Vandrovcova Jana , Mackenzie Chris-Ann , Ramasamy Adaikalavan , Ryten Mina , Smith Colin , Trabzuni Daniah , Weale Michael E ,   International Parkinson’s Disease Genomics Consortium, Noyce Alastair J , Kaiyrzhanov Rauan , Middlehurst Ben , Kia Demis A , Tan Manuela , Houlden Henry , Morris Huw R , Plun-Favreau Helene , Holmans Peter , Hardy John , Trabzuni Daniah , Bras Jose , Quinn John , Mok Kin Y , Kinghorn Kerri J , Billingsley Kimberley , Wood Nicholas W , Lewis Patrick , Guerreiro Rita , Lovering Ruth , R’Bibo Lea , Manzoni Claudia , Rizig Mie , Ryten Mina , Guelfi Sebastian , Escott-Price Valentina , Chelban Viorica , Foltynie Thomas , Williams Nigel , Shashakin Chingiz , Zharkinbekova Nazira , Zholdybayeva Elena , Aitkulova Akbota , Harvey Kirsten , Weale Michael E , Bhatia Kailash P , Webber Caleb , Hardy John , Botía Juan A , Ryten Mina 
Published: June 2020

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, frontal cortex and white matter modules, and nominal 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.