TY - JOUR
T1 - Association of Essential Tremor with Novel Risk Loci
T2 - A Genome-Wide Association Study and Meta-analysis
AU - Liao, Calwing
AU - Castonguay, Charles Etienne
AU - Heilbron, Karl
AU - Vuokila, Veikko
AU - Medeiros, Miranda
AU - Houle, Gabrielle
AU - Akçimen, Fulya
AU - Ross, Jay P.
AU - Catoire, Helene
AU - Diez-Fairen, Monica
AU - Kang, Jooeun
AU - Mueller, Stefanie H.
AU - Girard, Simon L.
AU - Hopfner, Franziska
AU - Lorenz, Delia
AU - Clark, Lorraine N.
AU - Soto-Beasley, Alexandra I.
AU - Klebe, Stephan
AU - Hallett, Mark
AU - Wszolek, Zbigniew K.
AU - Pendziwiat, Manuela
AU - Lorenzo-Betancor, Oswaldo
AU - Seppi, Klaus
AU - Berg, Daniela
AU - Vilariño-Güell, Carles
AU - Postuma, Ronald B.
AU - Bernard, Geneviève
AU - Dupré, Nicolas
AU - Jankovic, Joseph
AU - Testa, Claudia M.
AU - Ross, Owen A.
AU - Arzberger, Thomas
AU - Chouinard, Sylvain
AU - Louis, Elan D.
AU - Mandich, Paola
AU - Vitale, Carmine
AU - Barone, Paolo
AU - García-Martín, Elena
AU - Alonso-Navarro, Hortensia
AU - Agúndez, José A.G.
AU - Jiménez-Jiménez, Félix Javier
AU - Pastor, Pau
AU - Rajput, Alex
AU - Deuschl, Günther
AU - Kuhlenbaümer, Gregor
AU - Meijer, Inge A.
AU - Dion, Patrick A.
AU - Rouleau, Guy A.
N1 - Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/2
Y1 - 2022/2
N2 - Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485250 individuals, data for 483054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475877 control individuals (253785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET..
AB - Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485250 individuals, data for 483054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475877 control individuals (253785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET..
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U2 - 10.1001/jamaneurol.2021.4781
DO - 10.1001/jamaneurol.2021.4781
M3 - Article
C2 - 34982113
AN - SCOPUS:85122352691
SN - 2168-6149
VL - 79
SP - 185
EP - 193
JO - JAMA neurology
JF - JAMA neurology
IS - 2
ER -