Ástrós Thorarensen Skúladóttir is the project leader of the study in Communications Biology.

Scientists at deCODE genetics and their collaborators have revealed 12 sequence variants that affect the risk of  ET, (Essential tremor) providing important insights into its pathogenesis.

deCODE genetics/Amgen, and collaborators from Iceland, USA, UK, Denmark, Estonia, and Norway recently published the study: “WAS meta-analysis reveals key risk loci in essential tremor pathogenesis”, in Communications Biology. The study analyzed genetic data from roughly 2 million participants of whom 16,480 had essential tremor (ET).

ET (Essential tremor)  is one of the most common neurological disorders, affecting up to 5% of the population. Despite extensive research, sequence variants that contribute to its prevalence, familial clustering, and pathogenesis have remained unclear.

In the study, a genome-wide search revealed 12 sequence variants at 11 loci that affect the risk of ET, providing important insights into its pathogenesis. Seven genes were identified as candidate causal genes using functional evidence derived from transcriptomics and proteomics.

Of particular interest was CA3, which encodes carbonic anhydrase III. The inhibition of carbonic anhydrases has been shown to improve tremors and Primidone, one of the most widely used drug to treat ET patients, inhibits CA2, another carbonic anhydrase in close proximity to CA3. These findings support the therapeutical potential of carbonic anhydrase inhibitors in managing tremors.

Additionally, the study provided genetic insights into the involvement of GABA and dopaminergic neurons in the pathogenesis as well as biological processes like Rho GTPase signaling and stress response regulation. The research also demonstrated a genetic overlap between ET and Parkinson‘s Disease, depression and anxiety.

Given the phenotypic components and genetic liability shared by ET and Parkinson‘s Disease, the association with dopaminergic neurons, a crucial regulator of extrapyramidal movements, was anticipated. Interestingly, the findings also underscored the significance of stress response regulation, especially given the shared genetic risk shared by ET and anxiety. ET patients exhibit intensified tremors under stress and anti-anxiety drugs like Clonazepam prove highly affective in alleviating these tremors.

This progress not only enhances our knowledge of this complex and prevalent neurological disorder but can also form the basis of future investigations into treatment strategies and personalized interventions.