Exome-wide rare variant analysis in familial essential tremor.

Abstract

INTRODUCTION:

Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing.

METHODS:

We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes.

RESULTS:

Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders.

CONCLUSIONS:

We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

• Authors: Monica Diez-Fairen, Gabrielle Houle, Sara Ortega-Cubero, Sara Bandres-Ciga, Ignacio Alvarez, Maria Carcel, Laura Ibañez, Maria Victoria Fernandez, John P Budde, Jean-Rémi Trotta, Raúl Tonda, Jessica X Chong, Michael J Bamshad, Deborah A Nickerson, University of Washington Center for Mendelian Genomics (UWCMG), Miquel Aguilar, Juan P Tartari, Alexandre Gironell, Elena García-Martín, Jose Ag Agundez, Hortensia Alonso-Navarro, Felix Javier Jimenez-Jimenez, Manel Fernandez, Francesc Valldeoriola, Maria Jose Marti, Eduard Tolosa, Francisco Coria, Maria A Pastor, Carles Vilariño-Güell, Alex Rajput, Patrick A Dion, Carlos Cruchaga, Guy A Rouleau, Pau Pastor
• Journal: Parkinsonism & related disorders (Parkinsonism Relat Disord) Vol. 82 Pg. 109-116 (01 2021) ISSN: 1873-5126 [Electronic] England
• PMID: 33279834 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• MMP10 protein, human
• Matrix Metalloproteinase 10

Topics

• Adult
• Age of Onset
• Aged
• Aged, 80 and over
• Essential Tremor (genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Male
• Matrix Metalloproteinase 10 (genetics)
• Middle Aged
• Pedigree
• Exome Sequencing
• Young Adult