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 - Funding Information:
grants from Canadian Institutes of Health Research during the conduct of the study. Dr Heilbron is an employee at 23andMe. Drs Houle and J. Ross report grants from Canadian Institutes of Health Research during the conduct of the study. Dr Mueller was employed by Boehringer Ingelheim. Dr Wszolek reports support from the National Institute on Aging and National Institute of Neurological Disorders and Stroke; the Mayo Clinic Center for Regenerative Medicine; the Mayo Clinic Florida Focused Research Team Program; and gifts from the Sol Goldman Charitable Trust, the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson’s Research Foundation; he serves as principal investigator or co–principal investigator on Biohaven Pharmaceuticals, Inc, Neuraly, Inc, and Vigil Neuroscience, Inc grants; he serves as co–principal investigator of the Mayo Clinic American Parkinson Disease Association Center for Advanced Research and as an external advisory board member for Vigil Neuroscience, Inc. Dr Seppi reports research grants from FWF Austrian Science Fund, Michael J. Fox Foundation, and AOP Orphan Pharmaceuticals outside the submitted work as well as personal fees from Teva Neurosciences, UCB, AOP Orphan Pharmaceuticals, Lundbeck, Roche, Grünenthal,
Funding Information:
Stada, Licher Pharma, Biogen, AbbVie, and the International Parkinson and Movement Disorders Society outside the submitted work. Dr Berg reports personal fees from Bial, Biogen, Lundbeck, UCB, Desitin, the Finnish Neurological Society, GE Healthcare, the Movement Disorder Society, Zambon, Oxford Pharma Genesis Ltd, Preuss Foundation, Deutsche Parkinson Gesellschaft, Biomarin, Kyowa Kirin, Der Nervenarzt, and AbbVie as well as grants from UCB Pharma, Lundbeck, AbbVie, Novartis Pharma, Damp Foundation, Coppenrath Foundation, Stichting Parkinson Fonds, the Jan V. Appen Foundation, the Christa und Peter Thomsen Foundation, the Else-Kröner-Fresenius Foundation, Hoffmann La Roche, Icon Ltd + Biohaven Inc, and Deutsche Parkinson Gesellschaft outside the submitted work. Dr Postuma reports personal fees from Fonds de la Recherche en Sante, Takeda, Roche, Teva Neurosciences, Biogen, Theranexus, Jazz Pharmaceuticals, AbbVie, Janssen, Otsuko, Phytopharmics, Inception Sciences, Paladin, the International Parkinson and Movement Disorders Society, Merck, and Vaxxinity as well as grants from the Canadian Institute of Health Research, the Parkinson Society of Canada, the Weston-Garfield Foundation, the Michael J. Fox Foundation, the Webster Foundation, and the National Institutes of Health outside the submitted work. Dr Bernard reports serving as chair on the medical and scientific advisory board at the United Leukodystrophy Foundation and serving on the scientific advisory board at Pelizaeus-Merzbacher Disease Foundation; grants from Takeda/Shire, Ionis, Passage Bio, Bluebird Bio, Yaya Foundation for 4H Leukodystrophy, the Canadian Institutes of Health Research, Montreal Children’s Hospital Foundation, Fondation les Amis d’Elliot, Pelizaeus-Merzbacher Disease Foundation, Foundation of Stars, Healthy Brains Healthy Lives, Fondation le Tout pour Loo, Leuco-Action, Rare Diseases Foundation and British Columbia Children’s Foundation, Canada Summer Jobs, Association Lueur d’Espoir pour Ayden, Réseau de Médecine Génétique Appliquée, McGill University Health Center Research Ethics Board Department of Medicine Clinical Research Funding, and McGill University Health Center Research Ethics Board Research Institute; and personal fees from Ionis; other support from Passage Bio, Regenxbio, and the Canadian Institutes of Health Research outside the submitted work. Dr Louis reports personal fees from Sage Therapeutics, Praxis, Jazz Pharmaceuticals, and Clarion Healthcare outside the submitted work. Dr Deuschl reports personal fees from Boston Scientific, Jazz Pharmaceuticals, Functional Neuromodulation, and Thieme Publishers outside the submitted work. Dr Rouleau reports grants from the Canadian Institutes of Health Research during the conduct of the study. No other disclosures were reported.
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 -