{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:45:25Z","timestamp":1782819925047,"version":"3.54.5"},"reference-count":72,"publisher":"Ubiquity Press, Ltd.","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["FRN193300"],"award-info":[{"award-number":["FRN193300"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TOHM"],"abstract":"<jats:p>Essential Tremor (ET) is a highly heterogeneous movement disorder with a strong genetic basis. However, the etiology of ET is unclear, largely due to its clinical heterogeneity and frequently observed comorbidities.\nWe conducted a three-part study to investigate the genetic basis of ET in relation to co-occurring phenotypes, aiming to assess causal directionality and to clarify phenotypic heterogeneity. First, we used Mendelian Randomization (MR) to test for directional, causal relationships between ET and common co-occurring traits. We then identified pleiotropic single nucleotide polymorphisms (SNPs) shared between ET and these traits, mapped them to genes, and performed gene ontology enrichment analyses. Finally, we applied genomic structural equation modeling (g-SEM) to group traits by shared genetic variance and evaluate their influence on ET.\nMR analyses did not reveal causal relationships, likely due to high genetic pleiotropy. Gene enrichment analyses of shared SNPs suggested involvement of certain pathways, but these signals were driven by limited gene overlap. SEM identified a well-fitting latent model of shared genetic architecture, but it explained only ~2% (\u00b19%) of ET variance.\nOur findings suggest that ET and its comorbidities may share complex genetic architecture not captured by common variants alone. The limited variance explained by MR and SEM highlights the need for rare variant and multi-omics studies to better understand the biological mechanisms underlying ET and its heterogeneity.<\/jats:p>","DOI":"10.5334\/tohm.1168","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:42:18Z","timestamp":1777376538000},"page":"27","source":"Crossref","is-referenced-by-count":0,"title":["An Exploratory Analysis of Essential Tremor and Associated 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A.","family":"Rouleau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"3285","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"key20260428114214_B1","doi-asserted-by":"crossref","first-page":"04028","DOI":"10.7189\/jogh.11.04028","article-title":"The global prevalence of essential tremor, with emphasis on age and sex: A meta-analysis","volume":"11","year":"2021","journal-title":"J Glob Health"},{"issue":"1","key":"key20260428114214_B2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/mds.27121","article-title":"Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society","volume":"33","year":"2018","journal-title":"Movement Disorders"},{"issue":"Suppl 1","key":"key20260428114214_B3","first-page":"S92","article-title":"The etiology of essential tremor: Genes versus 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