eprintid: 10109621 rev_number: 32 eprint_status: archive userid: 608 dir: disk0/10/10/96/21 datestamp: 2020-09-09 15:44:04 lastmod: 2021-12-07 23:40:16 status_changed: 2020-09-09 15:44:04 type: article metadata_visibility: show creators_name: Mencacci, NE creators_name: Reynolds, R creators_name: Ruiz, SG creators_name: Vandrovcova, J creators_name: Forabosco, P creators_name: Sánchez-Ferrer, A creators_name: Volpato, V creators_name: UK Brain Expression Consortium, creators_name: International Parkinson’s Disease Genomics Consortium, creators_name: Weale, ME creators_name: Bhatia, KP creators_name: Webber, C creators_name: Hardy, J creators_name: Botía, JA creators_name: Ryten, M title: Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders ispublished: inpress divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F84 divisions: F85 divisions: F86 divisions: C08 divisions: D09 divisions: F99 divisions: D10 divisions: G10 divisions: D14 divisions: GA2 divisions: D13 divisions: G23 keywords: dystonia, medium-spiny neurons, network analysis, synaptic transmission, transcriptomic analysis note: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 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. date: 2020-08-21 date_type: published official_url: https://doi.org/10.1093/brain/awaa217 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1812195 doi: 10.1093/brain/awaa217 pii: 5895184 lyricists_name: Bhatia, Kailash lyricists_name: Chelban, Viorica lyricists_name: Foltynie, Thomas lyricists_name: Hardy, John lyricists_name: Harvey, Kirsten lyricists_name: Houlden, Henry lyricists_name: Kaiyrzhanov, Rauan lyricists_name: Kinghorn, Kerri lyricists_name: Lovering, Ruth lyricists_name: Manzoni, Claudia lyricists_name: Mok, Kin Ying lyricists_name: Morris, Huw lyricists_name: Plun-Favreau, Helene lyricists_name: Reynolds, Regina lyricists_name: Rizig, Mie lyricists_name: Ryten, Mina lyricists_name: Smalley, June lyricists_name: Tan, Manuela lyricists_name: Trabzuni, Daniah lyricists_name: Vandrovcova, Jana lyricists_name: Wood, Nicholas lyricists_id: KPBHA96 lyricists_id: VCHEL09 lyricists_id: TFOLT83 lyricists_id: JHARD28 lyricists_id: KHARV79 lyricists_id: HJHOU44 lyricists_id: RKAIY23 lyricists_id: KKING49 lyricists_id: RCLOV36 lyricists_id: CMANZ28 lyricists_id: BKMOK09 lyricists_id: HRMOR79 lyricists_id: HPLUN15 lyricists_id: RHREY66 lyricists_id: MAAAR33 lyricists_id: MBARI42 lyricists_id: JASMA87 lyricists_id: MTANX68 lyricists_id: DTRAB86 lyricists_id: JVAND74 lyricists_id: NWWOO43 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Brain article_number: awaa217 event_location: England citation: Mencacci, NE; Reynolds, R; Ruiz, SG; Vandrovcova, J; Forabosco, P; Sánchez-Ferrer, A; Volpato, V; ... Ryten, M; + view all <#> Mencacci, NE; Reynolds, R; Ruiz, SG; Vandrovcova, J; Forabosco, P; Sánchez-Ferrer, A; Volpato, V; UK Brain Expression Consortium; International Parkinson’s Disease Genomics Consortium; Weale, ME; Bhatia, KP; Webber, C; Hardy, J; Botía, JA; Ryten, M; - view fewer <#> (2020) Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain , Article awaa217. 10.1093/brain/awaa217 <https://doi.org/10.1093/brain%2Fawaa217>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10109621/1/awaa217.pdf