Brain Imaging Phenotypes Associated With Polygenic Risk For Essential Tremor

Abstract

AbstractEssential tremor (ET) is a common neurological disorder typically characterized by involuntary action tremor of the upper limb. ET has a strong genetic basis that may develop via the additive contribution of risk variants of varying frequencies. About 20% of ET liability can be explained by common variants which are incorporated in polygenic risk scores (PRS) that quantify individual risk level. Magnetic resonance imaging (MRI) has identified subtle abnormalities in the brains of people with ET. In particular, diffusion-weighted magnetic resonance imaging (dMRI) has been used to identify abnormalities in the connectivity and microstructure of white matter tracts in ET patients. In addition, diffusion and T1 MRI also demonstrate abnormalities in grey matter in essential tremor. However, these studies are performed in small samples and do not always replicate. Moreover, the mechanisms by which genetic risk affects the brain to render individuals vulnerable to ET remain unknown. In this study we probe the vulnerability of healthy people to ET by investigating the association of white matter dMRI, grey matter dMRI and morphometry with ET PRS in close to 30,000 individuals from the UK Biobank (UKB). Our results indicate significant effects of ET PRS on mean diffusivity, a measure of white matter microstructure, in cerebellar input tracts, thalamocortical motor tracts, and premotor and prefrontal white matter. We also found significant associations between ET PRS and grey matter tissue microstructure, in particular the red nucleus, caudate, putamen, and several regions of the motor thalamus, notably the ventral intermediate and ventrolateral nuclei. ET PRS was also associated with reduced grey matter volumes in several cortical and subcortical areas, notably affecting regions with functional projections to the cerebellar dentate nucleus. Further negative associations of ET PRS and grey matter volume were observed in the caudate, putamen, cerebellum and all brainstem subdivisions, including the inferior olivary nucleus, a known arrhythmogenic center in ET. We also found ET PRS associated reductions in volume of the ventral diencephalon, an area that includes the zona incerta, the crus cerebri, the lenticular fasciculus, and the medial lemniscus. The anomalies identified include the entire grey and white matter networks connected to surgical sites effective in treatment of ET. Furthermore, transcriptomic genomic structural equation modeling identified the 17q21.31 locus as relevant to the observed grey matter phenotype. Finally, comparison of low PRS individuals to a small number of patients with ET (N=49) in the UK Biobank revealed that most of the disruptions identified here are also present in ET patients. Altogether these results show that brain structural vulnerabilities in healthy people at risk of developing ET correspond to areas that are also 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.