TY - JOUR
T1 - GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis
AU - Skuladottir, Astros Th
AU - Stefansdottir, Lilja
AU - Halldorsson, Gisli H
AU - Stefansson, Olafur A
AU - Bjornsdottir, Anna
AU - Jonsson, Palmi
AU - Palmadottir, Vala
AU - Thorgeirsson, Thorgeir E
AU - Walters, G Bragi
AU - Gisladottir, Rosa S
AU - Bjornsdottir, Gyda
AU - Jonsdottir, Gudrun A
AU - Sulem, Patrick
AU - Gudbjartsson, Daniel F
AU - Knowlton, Kirk U
AU - Jones, David A
AU - Ottas, Aigar
AU - Pedersen, Ole B
AU - Didriksen, Maria
AU - Brunak, Søren
AU - Banasik, Karina
AU - Hansen, Thomas Folkmann
AU - Erikstrup, Christian
AU - DBDS Genomic Consortium
AU - Haavik, Jan
AU - Andreassen, Ole A
AU - Rye, David
AU - Igland, Jannicke
AU - Ostrowski, Sisse Rye
AU - Milani, Lili A
AU - Nadauld, Lincoln D
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Estonian Biobank
A2 - Nissen, Ioanna
A2 - Burgdorf, Kristoffer Sølvsten
A2 - Chalmer, Mona Ameri
A2 - Didriksen, Maria
A2 - Dowsett, Joseph
A2 - Feenstra, Bjarke
A2 - Geller, Frank
A2 - Hansen, Thomas Folkmann
A2 - Larsen, Margit Anita Hørup
A2 - Mikkelsen, Christina
A2 - Ostrowski, Sisse Rye
A2 - Schwinn, Michael
A2 - Thørner, Lise Wegner
N1 - © 2024. The Author(s).
PY - 2024/4/26
Y1 - 2024/4/26
N2 - 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.
AB - 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.
KW - Essential Tremor/genetics
KW - Humans
KW - Genome-Wide Association Study
KW - Genetic Predisposition to Disease
KW - Polymorphism, Single Nucleotide
KW - Genetic Loci
UR - https://www.scopus.com/pages/publications/85191631915
U2 - 10.1038/s42003-024-06207-4
DO - 10.1038/s42003-024-06207-4
M3 - Journal article
C2 - 38671141
SN - 2399-3642
VL - 7
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 504
ER -