학술논문
GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis
Document Type
article
Author
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
Source
Communications Biology, Vol 7, Iss 1, Pp 1-10 (2024)
Subject
Language
English
ISSN
2399-3642
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.