{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T22:07:53Z","timestamp":1773958073693,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T00:00:00Z","timestamp":1586131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Case\u2010control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome\u2010wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome\u2010wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome\u2010wide association study (TWAS) was done to identify novel risk genes for ET.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified several novel dysregulated genes, including <jats:italic>CACNA1A<\/jats:italic> and <jats:italic>SHF<\/jats:italic>. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion\u2010regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, <jats:italic>SHF<\/jats:italic>, is associated with a blood pressure medication (<jats:italic>P<\/jats:italic> = 9.3E\u201008), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in <jats:italic>SHF<\/jats:italic> when treated, suggesting it may rescue the underexpression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We found that calcium\u2010related pathways were enriched across the GWGAS, TWAS, and transcriptome. <jats:italic>SHF<\/jats:italic> was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of <jats:italic>SHF<\/jats:italic>. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. \u00a9 2020 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28031","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T05:55:14Z","timestamp":1586152514000},"page":"1153-1162","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor"],"prefix":"10.1002","volume":"35","author":[{"given":"Calwing","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Human Genetics McGill University  Montr\u00e9al Quebec Canada"},{"name":"Montreal Neurological Institute, McGill University  Montr\u00e9al Quebec 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University in Innsbruck  Innsbruck Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Neurology Christian\u2010Albrechts\u2010University  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Health Informations, University College London  London United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Hopfner","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospital Schleswig\u2010Holstein, Christian\u2010Albrechts\u2010Universit\u00e4t zu Kiel  Kiel Germany"},{"name":"Department of Neurology Hanover Medical School  Hanover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fcnther","family":"Deuschl","sequence":"additional","affiliation":[{"name":"Department of Neurology Kiel University  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregor","family":"Kuhlenb\u00e4eumer","sequence":"additional","affiliation":[{"name":"Department of Neurology Kiel University  Kiel Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Rajput","sequence":"additional","affiliation":[{"name":"Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region  Saskatoon Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick A.","family":"Dion","sequence":"additional","affiliation":[{"name":"Montreal Neurological Institute, McGill University  Montr\u00e9al Quebec Canada"},{"name":"Department of Neurology and Neurosurgery McGill University  Montr\u00e9al Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy A.","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University  Montr\u00e9al Quebec Canada"},{"name":"Montreal Neurological Institute, McGill University  Montr\u00e9al Quebec Canada"},{"name":"Department of Neurology and Neurosurgery McGill University  Montr\u00e9al Quebec 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