open access publication

Article, 2024

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

COMMUNICATIONS BIOLOGY, Volume 7, 1, 10.1038/s42003-024-06207-4

Contributors

Skuladottir, Astros Th. (Corresponding author) [1] [2] Stefansdottir, Lilja [1] Halldorsson, Gisli H. 0000-0001-7067-9862 [1] Stefansson, O. A. [1] Bjornsdottir, Anna [3] Jonsson, Palmi [2] [4] Palmadottir, Vala [4] Thorgeirsson, Thorgeir E. [1] Walters, G. Bragi [1] Gisladottir, Rosa S. [1] [2] Bjornsdottir, Gyda [1] Jonsdottir, GA [1] Sulem, P. [1] Gudbjartsson, Daniel F. [1] [2] Knowlton, K. U. 0000-0003-3544-4130 [5] [6] Jones, David A. 0000-0002-9770-1502 [5] [6] Ottas, Aigar [7] Pedersen, Ole Birger 0000-0002-3321-3972 [8] [9] Didriksen, M. 0000-0002-4856-496X [9] Brunak, Soren [9] Banasik, Karina 0000-0003-2489-2499 [9] Hansen, Thomas F. 0000-0001-6703-7762 [9] Erikstrup, Christian 0000-0001-6551-6647 [9] [10] Haavik, Jan 0000-0001-7865-2808 [11] [12] Andreassen, Ole A. [13] Rye, David [14] Igland, Jannicke [12] [15] Ostrowsk, Sisse R. 0000-0001-5288-3851 [9] Milani, Lili A. [9] Nadauld, Lincoln D. [5] [6] [16] Stefansson, Hreinn [1] Stefansson, Kari (Corresponding author) [1] [2] Estonian Biobank DBDS Genomic Consortium

Affiliations

  1. [1] AMGEN Inc, DeCODE Genet, Reykjavik, Iceland
    2. [NORA names: Iceland; Europe, Non-EU; Nordic; OECD];
  2. [2] Univ Iceland, Fac Engn & Nat Sci, Reykjavik, Iceland
    3. [NORA names: Iceland; Europe, Non-EU; Nordic; OECD];
  3. [3] Heilsuklasinn Clin, Reykjavik, Iceland
    4. [NORA names: Iceland; Europe, Non-EU; Nordic; OECD];
  4. [4] Landspitali Univ Hosp, Dept Geriatr Med, Reykjavik, Iceland
    5. [NORA names: Iceland; Europe, Non-EU; Nordic; OECD];
  5. [5] Intermt Heart Inst, Intermt Med Ctr, Salt Lake City, UT USA
    6. [NORA names: United States; America, North; OECD];

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.

Data Provider: Clarivate

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