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 - 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

AU - DBDS Genomic Consortium

N1 - Publisher Copyright: © 2024. The Author(s).

PY - 2024

Y1 - 2024

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.

U2 - 10.1038/s42003-024-06207-4

DO - 10.1038/s42003-024-06207-4

M3 - Journal article

C2 - 38671141

AN - SCOPUS:85191631915

VL - 7

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 504

ER -