Communications Biology (Apr 2024)
GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis
- Astros Th. Skuladottir,
- Lilja Stefansdottir,
- Gisli H. Halldorsson,
- Olafur A. Stefansson,
- Anna Bjornsdottir,
- Palmi Jonsson,
- Vala Palmadottir,
- Thorgeir E. Thorgeirsson,
- G. Bragi Walters,
- Rosa S. Gisladottir,
- Gyda Bjornsdottir,
- Gudrun A. Jonsdottir,
- Patrick Sulem,
- Daniel F. Gudbjartsson,
- Kirk U. Knowlton,
- David A. Jones,
- Aigar Ottas,
- Estonian Biobank,
- Ole B. Pedersen,
- Maria Didriksen,
- Søren Brunak,
- Karina Banasik,
- Thomas Folkmann Hansen,
- Christian Erikstrup,
- DBDS Genomic Consortium,
- Jan Haavik,
- Ole A. Andreassen,
- David Rye,
- Jannicke Igland,
- Sisse Rye Ostrowski,
- Lili A. Milani,
- Lincoln D. Nadauld,
- Hreinn Stefansson,
- Kari Stefansson
Affiliations
- Astros Th. Skuladottir
- deCODE genetics/Amgen Inc.
- Lilja Stefansdottir
- deCODE genetics/Amgen Inc.
- Gisli H. Halldorsson
- deCODE genetics/Amgen Inc.
- Olafur A. Stefansson
- deCODE genetics/Amgen Inc.
- Anna Bjornsdottir
- Heilsuklasinn Clinic
- Palmi Jonsson
- Faculty of Medicine, University of Iceland
- Vala Palmadottir
- Department of Internal Medicine, Landspitali University Hospital
- Thorgeir E. Thorgeirsson
- deCODE genetics/Amgen Inc.
- G. Bragi Walters
- deCODE genetics/Amgen Inc.
- Rosa S. Gisladottir
- deCODE genetics/Amgen Inc.
- Gyda Bjornsdottir
- deCODE genetics/Amgen Inc.
- Gudrun A. Jonsdottir
- deCODE genetics/Amgen Inc.
- Patrick Sulem
- deCODE genetics/Amgen Inc.
- Daniel F. Gudbjartsson
- deCODE genetics/Amgen Inc.
- Kirk U. Knowlton
- Intermountain Medical Center, Intermountain Heart Institute
- David A. Jones
- Precision Genomics, Intermountain Healthcare
- Aigar Ottas
- Estonian Genome Centre, Institute of Genomics, University of Tartu
- Estonian Biobank
- Ole B. Pedersen
- Department of Clinical Immunology, Zealand University Hospital
- Maria Didriksen
- Department of Clinical Immunology, Copenhagen University Hospital, Righospitale
- Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Thomas Folkmann Hansen
- Danish Headache Center, Department of Neurology, Copenhagen University Hospital, Righospitalet-Glostrup
- Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Righospitalet
- DBDS Genomic Consortium
- Jan Haavik
- Department of Biomedicine, University of Bergen
- Ole A. Andreassen
- Institute of Clinical Medicine, University of Oslo
- David Rye
- Emory Department of Neurology, Wesley Woods Health Center
- Jannicke Igland
- Department of Global Public Health and Primary Care, University of Bergen
- Sisse Rye Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
- Lili A. Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu
- Lincoln D. Nadauld
- Precision Genomics, Intermountain Healthcare
- Hreinn Stefansson
- deCODE genetics/Amgen Inc.
- Kari Stefansson
- deCODE genetics/Amgen Inc.
- DOI
- https://doi.org/10.1038/s42003-024-06207-4
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 10
Abstract
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.
