Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders
| Autor: | Regina H. Reynolds, Kerri J. Kinghorn, Lea R'Bibo, Alastair J. Noyce, Henry Houlden, Elena Zholdybayeva, Niccolo E. Mencacci, Patrick A. Lewis, Claudia Manzoni, Nazira Zharkinbekova, Daniah Trabzuni, Nicholas W. Wood, Sebastian Guelfi, John Hardy, Valentina Escott-Price, Rita Guerreiro, Ruth C. Lovering, Chris-Ann Mackenzie, Juan A. Botía, Álvaro Sánchez-Ferrer, John P. Quinn, Viola Volpato, Rauan Kaiyrzhanov, Peter Holmans, Caleb Webber, Huw R. Morris, Sonia Garcia Ruiz, Kirsten Harvey, Nigel Williams, Thomas Foltynie, Colin Smith, Viorica Chelban, Ben Middlehurst, Kin Y. Mok, Karishma D’Sa, Adaikalavan Ramasamy, Chingiz Shashakin, Kailash P. Bhatia, Helene Plun-Favreau, Jana Vandrovcova, Mina Ryten, Manuela Tan, Mie Rizig, Kimberley Billingsley, Demis A. Kia, Akbota Aitkulova, Paola Forabosco, Jose Bras, Michael E. Weale |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Substantia nigra Neurological disorder Biology Medium spiny neuron 03 medical and health sciences 0302 clinical medicine Neurobiology otorhinolaryngologic diseases medicine synaptic transmission Humans Gene Regulatory Networks Psychiatry network analysis transcriptomic analysis Dystonia Neurons AcademicSubjects/SCI01870 Putamen Mental Disorders Original Articles Human brain medicine.disease nervous system diseases 030104 developmental biology medicine.anatomical_structure Neurology Schizophrenia Dystonic Disorders Major depressive disorder AcademicSubjects/MED00310 Neurology (clinical) medium-spiny neurons Erratum Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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. See Busch and Klein (doi:10.1093/brain/awaa253) for a scientific commentary on this article. Mencacci et al. show that multiple dystonia genes are functionally related and likely contribute to modulation of synaptic signalling in striatal, dopaminergic and frontal cortical neurons. They also demonstrate a genetic relationship between dystonia and psychiatric disorders including depression, OCD and schizophrenia. |
| Databáze: | OpenAIRE |
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