GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis
Ástrós Skúladóttir, Lilja Stefánsdóttir, Gísli H. Halldórsson, Ólafur Andri Stefánsson, Anna Bjornsdottir, Pálmi V. Jónsson, Vala Palmadottir, Thorgeir E. Thorgeirsson, G. Bragi Walters, Rósa S. Gísladóttir, Gyða Björnsdóttir, Guðrún A. Jónsdóttir, Patrick Sulem, Daníel F. Guðbjartsson, Kirk U. Knowlton, David A. Jones, Aigar Ottas, Estonian Biobank, Tõnu Esko, Reedik Mägi, Mari Nelis, Georgi Hudjashov, Ole Birger Pedersen, Maria Didriksen, Søren Brunak, Karina Banasik, Thomas Folkmann Hansen, Christian Erikstrup, Jakob Thaning Bay, Jens Kjærgaard Boldsen, Thorsten Brodersen, Kristoffer Sølvsten Burgdorf, Mona Ameri Chalmer, Khoa Manh Dinh, Joseph Dowsett, Bjarke Feenstra, Frank Geller, Daníel F. Guðbjartsson, Lotte Hindhede, Henrik Hjalgrim, Rikke Louise Jacobsen, Gregor B. E. Jemec, Bitten Aagaard Jensen, Katrine Kaspersen, Bertram Kjerulff, Lisette J. A. Kogelman, Margit Anita Hørup Larsen, Ioannis Louloudis, Agnete Troen Lundgaard, Susan Mikkelsen, Christina Mikkelsen, Janna Nissen, Mette Nyegaard, Ole Birger Pedersen, Alexander Pil Henriksen, Palle Duun Rohde, Klaus Rostgaard, Michael Schwinn, Hreinn Stefánsson, Erik Sørensen, Unnur Þorsteinsdóttir, Lise Wegner Thørner, Mie Topholm Bruun, Henrik Ullum, Thomas Werge, David Westergaard, Jan Haavik, Ole A. Andreassen, David B. Rye, Jannicke Igland, Sisse Rye Ostrowski, Lili Milani, Lincoln Nadauld, Hreinn Stefánsson, Kāri Stefánsson
Abstract
Essential 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.