Brain Imaging Phenotypes Associated with Polygenic Risk for Essential Tremor

Essential tremor (ET) is a common movement disorder with a strong genetic basis. Magnetic resonance imaging (MRI), particularly diffusion-weighted MRI (dMRI) and T1 MRI, have been used to identify brain abnormalities of ET patients. However, the mechanisms by which genetic risk affects the brain to render individuals vulnerable to ET remain unknown. We aimed to understand how ET manifests by identifying presymptomatic brain vulnerabilities driven by ET genetic risk. We probed the vulnerability of healthy people towards ET by investigating the association of morphometry, and white and grey matter dMRI with ET in polygenic risk scores (PRS) in roughly 30,000 individuals from the UK Biobank (UKB). Our results indicate significant effects of ET-PRS with mean diffusivity, fractional anisotropy, free water, radial diffusivity, and axial diffusivity in white matter tracts implicated in movement control. We found significant associations between ET-PRS and grey matter tissue microstructure, including the red nucleus, caudate, putamen, and motor thalamus. ET-PRS was associated with reduced grey matter volumes in several cortical and subcortical areas including the cerebellum. Identified anomalies included networks connected to surgical sites effective in ET treatment. Finally, in a secondary analysis, low PRS individuals compared with a small number of patients with ET (N = 49) in the UKB revealed many structural differences. Brain structural vulnerabilities in healthy people at risk of developing ET correspond to areas known to be involved in the pathology of ET. High genetic risk of ET seems to disrupt ET brain networks even in the absence of overt symptoms of ET. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.