Exome-wide rare variant analysis in familial essential tremor
Por:
Diez-Fairen, M, Houle, G, Ortega-Cubero, S, Bandres-Ciga, S, Alvarez, I, Carcel, M, Ibanez, L, Fernandez, MV, Budde, JP, Trotta, JR, Tonda, R, Chong, JX, Bamshad, MJ, Nickerson, DA, Aguilar, M, Tartari, JP, Gironell, A, Garcia-Martin, E, Agundez, JAG, Alonso-Navarro, H, Jimenez-Jimenez, FJ, Fernandez, M, Valldeoriola, F, Marti, MJ, Tolosa, E, Coria, F, Pastor, MA, Vilarino-Guell, C, Rajput, A, Dion, PA, Cruchaga, C, Rouleau, GA, Pastor, P, UMCMG
Publicada:
1 ene 2021
Resumen:
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.
Filiaciones:
Diez-Fairen, M:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Houle, G:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada
Ortega-Cubero, S:
Hosp Univ Burgos, Dept Neurol & Neurosurg, Burgos, Spain
Bandres-Ciga, S:
NIA, Mol Genet Sect, Lab Neurogenet, NIH, Bldg 10, Bethesda, MD 20892 USA
Inst Invest Biosanitaria Granada Ibs GRANADA, Granada, Spain
Alvarez, I:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Carcel, M:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Ibanez, L:
Washington Univ, Sch Med, Dept Psychiat, NeuroGen & Informat, St Louis, MO 63110 USA
Fernandez, MV:
Washington Univ, Sch Med, Dept Psychiat, NeuroGen & Informat, St Louis, MO 63110 USA
Budde, JP:
Washington Univ, Sch Med, Dept Psychiat, NeuroGen & Informat, St Louis, MO 63110 USA
Trotta, JR:
Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat, Ctr Nacl Anal Genbm CNAG CRG, Barcelona, Spain
Univ Pompeu Fabra UPF, Barcelona, Spain
Tonda, R:
Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat, Ctr Nacl Anal Genbm CNAG CRG, Barcelona, Spain
Univ Pompeu Fabra UPF, Barcelona, Spain
Chong, JX:
Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA
Bamshad, MJ:
Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA
Seattle Childrens Hosp, Seattle, WA 98105 USA
Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
Nickerson, DA:
Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
Aguilar, M:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Tartari, JP:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
Gironell, A:
Hosp Santa Creu & Sant Pau, Movement Disorders Unit, Neurol Dept, Barcelona 08026, Spain
St Pau Biomed Res Inst, Barcelona 08026, Spain
Garcia-Martin, E:
Inst Salud Carlos III, UNEx ARADyAL, Univ Inst Mol Pathol Biomarkers, Caceres, Spain
Agundez, JAG:
Inst Salud Carlos III, UNEx ARADyAL, Univ Inst Mol Pathol Biomarkers, Caceres, Spain
Alonso-Navarro, H:
Hosp Univ Sureste, Sect Neurol, Madrid, Spain
Jimenez-Jimenez, FJ:
Hosp Univ Sureste, Sect Neurol, Madrid, Spain
Fernandez, M:
Washington Univ, Sch Med, Dept Psychiat, NeuroGen & Informat, St Louis, MO 63110 USA
Univ Barcelona, Minist Sci Innovat & Univ, Maria Maeztu Unit Excellence, Inst Neurosci, MDM-2017-0729, Barcelona, Spain
Valldeoriola, F:
IDIBAPS, Hosp Clin, Dept Neurol, Parkinsons Dis & Movement Disorders Unit, Barcelona, Spain
Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Marti, MJ:
IDIBAPS, Hosp Clin, Dept Neurol, Parkinsons Dis & Movement Disorders Unit, Barcelona, Spain
Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Tolosa, E:
IDIBAPS, Hosp Clin, Dept Neurol, Parkinsons Dis & Movement Disorders Unit, Barcelona, Spain
Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Coria, F:
Son Espases Univ Hosp, Serv Neurol, Clin Nervous Disorders, Palma De Mallorca, Spain
Pastor, MA:
Clin Univ Navarra, Dept Neurol, Pamplona, Spain
Vilarino-Guell, C:
Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada
Rajput, A:
Univ Saskatchewan, Saskatchewan Hlth Author, Saskatchewan Movement Disorders Program, Saskatoon, SK, Canada
Dion, PA:
McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada
Cruchaga, C:
Washington Univ, Sch Med, Dept Psychiat, NeuroGen & Informat, St Louis, MO 63110 USA
Rouleau, GA:
McGill Univ, Dept Human Genet, Montreal, PQ, Canada
McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada
Pastor, P:
Univ Hosp Matua Terrassa, Movement Disorders Unit, Fundacio Docencia & Recerca MutuaTerrassa, Dept Neurol, Barcelona, Spain
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