GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis
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Published:2024-04-26
Issue:1
Volume:7
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Skuladottir Astros Th.ORCID, Stefansdottir Lilja, Halldorsson Gisli H.ORCID, Stefansson Olafur A.ORCID, Bjornsdottir Anna, Jonsson Palmi, Palmadottir Vala, Thorgeirsson Thorgeir E., Walters G. BragiORCID, Gisladottir Rosa S., Bjornsdottir GydaORCID, Jonsdottir Gudrun A., Sulem PatrickORCID, Gudbjartsson Daniel F.ORCID, Knowlton Kirk U., Jones David A., Ottas Aigar, , Esko Tõnu, Mägi Reedik, Nelis Mari, Hudjashov Georgi, Pedersen Ole B.ORCID, Didriksen MariaORCID, Brunak SørenORCID, Banasik KarinaORCID, Hansen Thomas FolkmannORCID, Erikstrup ChristianORCID, , Bay Jakob, Boldsen Jens Kjærgaard, Brodersen Thorsten, Burgdorf Kristoffer, Chalmer Mona Ameri, Dinh Khoa Manh, Dowsett Joseph, Feenstra Bjarke, Geller Frank, Gudbjartsson Daniel, Hindhede Lotte, Hjalgrim Henrik, Jacobsen Rikke Louise, Jemec Gregor, Jensen Bitten Aagaard, Kaspersen Katrine, Kjerulff Bertram Dalskov, Kogelman Lisette, Larsen Margit Anita Hørup, Louloudis Ioannis, Lundgaard Agnete, Mikkelsen Susan, Mikkelsen Christina, Nissen Ioanna, Nyegaard Mette, Pedersen Ole Birger, Henriksen Alexander Pil, Rohde Palle Duun, Rostgaard Klaus, Schwinn Michael, Stefánsson Hreinn, Sørensen Erik, Þorsteinsdóttir Unnur, Thørner Lise Wegner, Bruun Mie Topholm, Ullum Henrik, Werge Thomas, Westergaard David, Haavik JanORCID, Andreassen Ole A., Rye David, Igland Jannicke, Ostrowski Sisse RyeORCID, Milani Lili A.ORCID, Nadauld Lincoln D., Stefansson HreinnORCID, Stefansson KariORCID
Abstract
AbstractEssential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.
Publisher
Springer Science and Business Media LLC
Reference84 articles.
1. Louis, E. D. & Ferreira, J. J. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov. Disord. 25, 534–541 (2010). 2. Lorenz, D., Poremba, C., Papengut, F., Schreiber, S. & Deuschl, G. The psychosocial burden of essential tremor in an outpatient- and a community-based cohort. Eur. J. Neurol. 18, 972–979 (2011). 3. Bhatia, K. P. et al. Consensus Statement on the Classification of Tremors. From the Task Force on Tremor of the International Parkinson and Movement Disorder Society. Mov. Disord. 33, 75 (2018). 4. Haerer, A. F., Anderson, D. W. & Schoenberg, B. S. Prevalence of Essential Tremor: Results From the Copiah County Study. Arch. Neurol. 39, 750–751 (1982). 5. Louis, E. D. et al. Differences in the prevalence of essential tremor among elderly African Americans, whites, and Hispanics in northern Manhattan, NY. Arch. Neurol. 52, 1201–1205 (1995).
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