{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:01:32Z","timestamp":1791489692657,"version":"4.3.4"},"reference-count":93,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lundbeck Fonden","award":["R100-2011-9332"],"award-info":[{"award-number":["R100-2011-9332"]}]},{"name":"Region Hovedstadens Forskningsfond til Sundhedsforskning","award":["2024-0059"],"award-info":[{"award-number":["2024-0059"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Tic spectrum disorder (TSD), encompassing Tourette syndrome and chronic tic disorder, is a childhood-onset neurodevelopmental condition with complex genetic and environmental contributions. Heritable components have been implicated in TSD, but no clear genetic mechanisms have been identified. Significant aspects of TSD etiology remain unclear, with key uncertainties concerning the role of environmental influences in its development. In this study, we aimed to identify environmentally induced epigenomic and transcriptomic changes contributing to TSD pathology by investigating genetically similar monozygotic twins discordant for TSD. Methods: To investigate environmentally driven mechanisms, we analyzed peripheral blood from eleven monozygotic twin pairs, either discordant or concordant for TSD, using RNA sequencing and DNA methylation analysis. Results: Differential expression analysis identified a dozen differentially expressed genes between TSD and non-TSD individuals, most of which were long non-coding RNAs or pseudogenes. Expression of the small RNA gene RNY1 was significantly associated with tic severity, suggesting involvement of immune-related processes. DNA methylation (DNAm) analysis revealed ~30,000 probes with a nominal p &lt; 0.05, however none of these were significant after multiple testing correction. Expression quantitative trait methylation (eQTM) analysis identified 236 methylation-associated genes. Gene set enrichment analysis demonstrated broad downregulation in TSD individuals for pathways related to translation, RNA processing, and neurobiological functions, with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including ribosome, nucleocytoplasmic transport, pluripotency signaling, and nicotine addiction. Conclusions: These results suggest that environmentally influenced gene expression may contribute to TSD pathogenesis through dysregulation of immune and neuronal pathways. Despite a small sample size, the monozygotic twin design provides strong control for genetic background and identifies significant differences that contribute to the understanding of the underlying molecular mechanisms of TSD.<\/jats:p>","DOI":"10.3390\/genes17010097","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T11:27:58Z","timestamp":1768908478000},"page":"97","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptome- and Epigenome-Wide Association Studies of Tic Spectrum Disorder in Discordant Monozygotic Twins"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0524-6663","authenticated-orcid":false,"given":"Jonas","family":"Dalsberg","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine","family":"Jespersgaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-4300","authenticated-orcid":false,"given":"Amanda M.","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2589-1781","authenticated-orcid":false,"given":"Anna Maria","family":"Asplund","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0636-8845","authenticated-orcid":false,"given":"Frederik Otzen","family":"Bagger","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-1865","authenticated-orcid":false,"given":"Nanette M.","family":"Debes","sequence":"additional","affiliation":[{"name":"National Tourette Clinic, Department of Pediatrics, Copenhagen University Hospital, 2730 Herlev, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-0030","authenticated-orcid":false,"given":"Qihua","family":"Tan","sequence":"additional","affiliation":[{"name":"Research Unit for Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, 5230 Odense, Denmark"},{"name":"Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4777-5802","authenticated-orcid":false,"given":"Zeynep","family":"T\u00fcmer","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-3670","authenticated-orcid":false,"given":"Mathis","family":"Hildonen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1474-4422(22)00303-9","article-title":"Tourette Syndrome: Clinical Features, Pathophysiology, and Treatment","volume":"22","author":"Johnson","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1002\/mds.22504","article-title":"Immunopathogenic Mechanisms in Tourette Syndrome: A Critical Review","volume":"24","author":"Martino","year":"2009","journal-title":"Mov. 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