Astros Thorarensen Skuladottir and Kari Stefansson
Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In a genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identified 12 sequence variants at 11 loci, of which 8 are novel. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlighted seven putative causal genes at these loci, including CA3 and CPLX1. We found a coding variant in CA3, p.Val31Ile, that associates with decreased risk of ET, CA3 expression in skeletal muscles, and carbonic anhydrase III levels in plasma, providing biological evidence supporting the potential effectiveness of carbonic anhydrase inhibitors in improving tremor control for ET patients. We also found an intronic variant in CPLX1, encoding Complexin-1, that confers risk of ET. Complexin-1 enhances neurotransmitter release and shows several indications of its involvement in the pathogenesis of ET, evidenced by its association with myoclonic epilepsy and the extreme early-onset ataxia in knockout mice. Performing pathway analysis has previously been challenging for ET due to insufficient data and a lack of significant genetic loci. We were able to identify, through a gene-set enrichment analysis, a significant association with dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling and stress response regulation. Interestingly, genetic correlation revealed a positive association between ET and anxiety, underscoring the need to regulate stress response in patients. This research reveals key risk loci providing insights in ET pathogenesis and highlights CA3 as a potential therapeutic target.
