RT Journal Article
T1 Exome-wide rare variant analysis in familial essential tremor.
A1 Diez-Fairen, Monica
A1 Houle, Gabrielle
A1 Ortega-Cubero, Sara
A1 Bandres-Ciga, Sara
A1 Alvarez, Ignacio
A1 Carcel, Maria
A1 Ibañez, Laura
A1 Fernandez, Maria Victoria
A1 Budde, John P
A1 Trotta, Jean-Remi
A1 Tonda, Raul
A1 Chong, Jessica X
A1 Bamshad, Michael J
A1 Nickerson, Deborah A
A1 Aguilar, Miquel
A1 Tartari, Juan P
A1 Gironell, Alexandre
A1 Garcia-Martin, Elena
A1 Agundez, Jose Ag
A1 Alonso-Navarro, Hortensia
A1 Jimenez-Jimenez, Felix Javier
A1 Fernandez, Manel
A1 Valldeoriola, Francesc
A1 Marti, Maria Jose
A1 Tolosa, Eduard
A1 Coria, Francisco
A1 Pastor, Maria A
A1 Vilariño-Güell, Carles
A1 Rajput, Alex
A1 Dion, Patrick A
A1 Cruchaga, Carlos
A1 Rouleau, Guy A
A1 Pastor, Pau
K1 Essential tremor
K1 Genetic risk
K1 MMP10
K1 Rare variants
K1 WES
AB 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. 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. 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. 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.
PB Elsevier Ltd
YR 2020
FD 2020-11-21
LK http://hdl.handle.net/10668/16738
UL http://hdl.handle.net/10668/16738
LA en
NO Diez-Fairen M, Houle G, Ortega-Cubero S, Bandres-Ciga S, Alvarez I, Carcel M, et al. Exome-wide rare variant analysis in familial essential tremor. Parkinsonism Relat Disord. 2021 Jan;82:109-116.
NO The authors thank the subjects and their families whose help and participation made this work possible. This study was funded by the Spanish Ministry of Science and Innovation to P.P. [SAF2013-47939-R (2013–2018)], and M.F. was funded by the María de Maeztu programme (grant MDM-2017-0729). Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors also acknowledge the technical and human support provided by the Sequencing and Genotyping Unit of the Genomics Facility (SGIker) of UPV/EHU, as well as European funding (ERDF and ESF).
DS RISalud
RD Apr 4, 2025