Poster Presentation GENEMAPPERS 2026

Comprehensive GWAS meta-analysis expands the genetic landscape of essential tremor with 47 novel risk loci (#76)

Natalia Ogonowski 1 , Fangyuan Cao 1 , Victor Flores-Ocampo 1 , Sofia Salazar-Magaña 2 3 , Mathias Seviiri 2 , Liyang Song 4 , Sam Nayler 2 , Jason Kugelman 2 , Gabriel Cuellar-Partida 5 , Stuart MacGregor 2 , Hae Kyung Im 3 , Ian Harding 2 , Puya Gharahkhani 2 , Nicholas Martin 2 , Kishore Kumar 6 , Jian Yang 3 , Santiago Diaz-Torres 1 , Miguel Renteria 1
  1. Computational Neurogenomics Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  2. QIMR Berghofer, Herston, QLD, Australia
  3. Department of Medicine, Section of Genetic Medicine, University of Chicago, Chicago, USA
  4. School of Life Sciences, Westlake University, Hangzhou, China
  5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
  6. Translational Neurogenomics Group, Genomics and Inherited Disease Program, Garvan Institute of Medical Research, NSW, Australia

Background
Essential tremor (ET), the most common movement disorder, affects ~4% of adults over 40, yet its genetic and neurobiological basis remains unclear.

Methods
We conducted a genome-wide association meta-analysis including 20,268 ET cases and 723,761 neurologically healthy controls of European ancestry (Million Veteran Program, 23andMe, All of Us), testing ~22 million quality-controlled SNPs. SNP heritability was estimated using LD score regression. We performed genetic correlation analyses across 2,800+ traits (FDR < 0.05), integrated transcriptomic data via S-PrediXcan/S-MultiXcan, fine-mapped genes with FOCUS, assessed colocalization with GTEx v8 brain eQTLs, and examined spatial/cellular enrichment using gsMap. Polygenic risk scores (PRS) were evaluated in UK Biobank (EUR) and All of Us (AFR/AMR).

Results
We identified 50 independent genome-wide significant loci, 47 novel, with SNP-based heritability of 18.5% (liability scale). ET showed positive genetic correlations with Parkinson’s disease, restless legs syndrome, and neuroticism, and negative correlations with ventral diencephalon and cerebellar volumes. Transcriptome-wide and fine-mapping analyses highlighted BACE2 and S100A13 as top candidates, with colocalization supporting BACE2, S100A13, PCDH9, and HARS as likely causal. Cell-type enrichment implicated excitatory cortical and hippocampal neurons, astrocytes, and microglia, aligning with a cerebellar–cortical circuit model. PRS predicted ET risk in European ancestry (OR = 2.15, AUC = 0.69), with moderate performance in admixed American (OR = 1.99, AUC = 0.67) and limited in African ancestry (OR = 1.17, AUC = 0.52).

Interpretation
This largest ET GWAS expands the genetic landscape and links risk to cerebellar-diencephalic structure and excitatory neuron programs, implicating glial contributions. Convergent evidence nominates BACE2, S100A13, HARS, and PCDH9 as actionable targets and supports PRS-based risk prediction in European populations. Broader ancestral representation remains essential for equitable genomic medicine.