Association of Essential Tremor With Novel Risk Loci A Genome-Wide Association Study and Meta-analysis

被引：13

作者：

Liao, Calwing ^{[1
,2
]}

Castonguay, Charles-Etienne ^{[1
,2
,3
]}

Heilbron, Karl ^{[4
]}

Vuokila, Veikko ^{[2
]}

Medeiros, Miranda ^{[2
]}

Houle, Gabrielle ^{[1
,2
]}

Akcimen, Fulya ^{[1
,2
]}

Ross, Jay P. ^{[1
,2
]}

Catoire, Helene ^{[2
]}

Diez-Fairen, Monica ^{[5
,6
]}

Kang, Jooeun ^{[7
]}

Mueller, Stefanie H. ^{[8
]}

Girard, Simon L. ^{[9
,10
]}

Hopfner, Franziska ^{[11
]}

Lorenz, Delia ^{[12
]}

Clark, Lorraine N. ^{[13
]}

Soto-Beasley, Alexandra I. ^{[14
]}

Klebe, Stephan ^{[15
,16
]}

Hallett, Mark ^{[17
]}

Wszolek, Zbigniew K. ^{[18
]}

Pendziwiat, Manuela ^{[19
,20
]}

Lorenzo-Betancor, Oswaldo ^{[21
,22
]}

Seppi, Klaus ^{[23
]}

Berg, Daniela ^{[24
]}

Vilarino-Guell, Carles ^{[25
]}

Postuma, Ronald B. ^{[10
]}

Bernard, Genevieve ^{[10
,26
,27
,28
,29
]}

Dupre, Nicolas ^{[30
]}

Jankovic, Joseph ^{[31
,32
]}

Testa, Claudia M. ^{[33
]}

Ross, Owen A. ^{[34
,35
]}

Arzberger, Thomas ^{[36
,37
]}

Chouinard, Sylvain ^{[38
]}

Louis, Elan D. ^{[39
]}

Mandich, Paola ^{[40
,41
]}

Vitale, Carmine ^{[42
]}

Barone, Paolo ^{[43
]}

Garcia-Martin, Elena ^{[44
]}

Alonso-Navarro, Hortensia ^{[45
]}

Agundez, Jose A. G. ^{[44
]}

Jimenez-Jimenez, Felix Javier ^{[45
]}

Pastor, Pau ^{[5
]}

Rajput, Alex ^{[46
]}

Deuschl, Gunther ^{[47
]}

Kuhlenbaumer, Gregor ^{[24
]}

Meijer, Inge A. ^{[48
]}

Dion, Patrick A. ^{[2
,3
]}

Rouleau, Guy A. ^{[1
,2
,3
]}

机构：

[1] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[2] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada

[3] McGill Univ, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada

[4] 23andMe Inc, Sunnyvale, CA USA

[5] Univ Hosp Mutua Terrassa, Fundacio Docencia Recerca Mutua Terrassa, Barcelona, Spain

[6] Univ Hosp Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain

[7] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med,Vanderbilt Genet Inst, Nashville, TN USA

[8] UCL, Inst Hlth Informat, London, England

[9] Univ Quebec Chicoutimi, Dept Sci Fondament, Saguenay, PQ, Canada

[10] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[11] Hannover Med Sch, Dept Neurol, Hannover, Germany

[12] Univ Wurzburg, Univ Childrens Hosp, Wurzburg, Germany

[13] Columbia Univ, Taub Inst, Dept Pathol & Cell Biol, New York, NY USA

[14] Mayo Clin Florida, Dept Neurol, Jacksonville, FL USA

[15] Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany

[16] Univ Hosp Essen, Dept Neurol, Essen, Germany

[17] NINDS, Intramural Res Program, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[18] Mayo Clin Florida, Dept Neurol, Jacksonville, FL USA

[19] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[20] Univ Kiel, Univ Med Ctr Schleswig Holstein, Dept Neuropediatr, Kiel, Germany

[21] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA

[22] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA

[23] Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria

[24] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Neurol, Kiel, Germany

[25] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada

[26] Montreal Childrens Hosp, Div Pediat Neurol, Dept Pediat, Montreal, PQ, Canada

[27] Montreal Childrens Hosp, Dept Neurol & Neurosurg, Div Pediat Neurol, Montreal, PQ, Canada

[28] McGill Univ, Hlth Ctr, Child Hlth & Human Dev Program, Res Inst, Montreal, PQ, Canada

[29] McGill Univ, Hlth Ctr, Montreal Childrens Hosp, Div Med Genet,Dept Specialized Med, Montreal, PQ, Canada

[30] Univ Laval, Fac Med, Ctr Hosp Univ Quebec Enfant Jesus, Quebec City, PQ, Canada

[31] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA

[32] Baylor Coll Med, Dept Neurol, Movement Disorders Clin, Houston, TX 77030 USA

[33] Virginia Commonwealth Univ, Dept Neurol, Parkinsons & Movement Disorders Ctr, Richmond, VA USA

[34] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA

[35] Mayo Clin Florida, Dept Clin Genom, Jacksonville, FL USA

[36] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Psychiat & Psychotherapy, Munich, Germany

[37] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany

[38] Ctr Hosp Univ Montreal, Unite Troubles Mouvement Andre Barbeau, Montreal, PQ, Canada

[39] Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA

[40] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet & Maternal, Genoa, Italy

[41] Ist Ricovero & Cura Carattere Sci Policlin, Genoa, Italy

[42] Univ Parthenope, Dept Motor Sci & Wellness, Naples, Italy

[43] Univ Salerno, Ctr Neurodegenerat Dis CEMAND, Dept Med Surg & Dent, Scuola Med Salernitana, Salerno, Italy

[44] Univ Inst Mol Pathol Biomarkers, ARADyAL Inst Salud Carlos III, UNEx, Caceres, Spain

[45] Hosp Univ Sureste, Sect Neurol, Madrid, Spain

[46] Univ Saskatchewan, Saskatoon Hlth Author, Saskatoon, SK, Canada

[47] Univ Kiel, Univ Med Ctr Schleswig Holstein, Dept Neurol, Kiel, Germany

[48] Univ Montreal, Dept Neurosci & Pediat, Montreal, PQ, Canada

来源：

JAMA NEUROLOGY | 2022年 / 79卷 / 02期

关键词：

LD SCORE REGRESSION; BETA; LINGO1; HERITABILITY; EXPRESSION; MUTATIONS; RS9652490; BRAIN; BACE2; TWINS;

D O I：

10.1001/jamaneurol.2021.4781

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 485 250 individuals, data for 483 054 passed data quality control and were used. MAIN OUTCOMES AND MEASURES Genotypes of common variants associated with risk of ET. RESULTS Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [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 x 10(-8)) and depression (r, 0.12; P = 9.78 x 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.

引用

页码：185 / 193

页数：9

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Deuschl, Guenther
Louis, Elan D.
Kuhlenbaeumer, Gregor
Rouleau, Guy A.
[J]. BRAIN, 2016, 139 : 3163 - 3169
[5] Genome-wide association study in essential tremor identifies three new loci
Mueller, S. H.
Girard, S. L.
Hopfner, F.
Merner, N. D.
Bourassa, C. V.
Lorenz, D.
Clark, L. N.
Tittmann, L.
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Schneider, S. A.
Hodgkinson, C. A.
Lieb, W.
Franke, A.
Wszolek, Z. K.
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Lorenzo-Betancor, O.
Poewe, W.
Ortega-Cubero, S.
Seppi, K.
Rajput, A.
Hussl, A.
Rajput, A. H.
Berg, D.
Dion, P. A.
Wurster, I.
Shulman, J. M.
Srulijes, K.
Haubenberger, D.
Pastor, P.
Vilarino-Guell, C.
Postuma, R. B.
Bernard, G.
Ladwig, K.
Dupre, N.
Jankovic, J.
Strauch, K.
Panisset, M.
Winkelmann, J.
Testa, C. M.
Reischl, E.
Zeuner, K. E.
Ross, O. A.
Arzberger, T.
Chouinard, S.
Deuschl, G.
Louis, E. D.
Kuhlenbaumer, G.
Rouleau, G. A.
[J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2018, 26 : 388 - 389
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Nyholt, Dale R.
Low, Siew-Kee
Anderson, Carl A.
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Morris, Andrew P.
MacGregor, Stuart
Gordon, Scott D.
Henders, Anjali K.
Martin, Nicholas G.
Attia, John
Holliday, Elizabeth G.
McEvoy, Mark
Scott, Rodney J.
Kennedy, Stephen H.
Treloar, Susan A.
Missmer, Stacey A.
Adachi, Sosuke
Tanaka, Kenichi
Nakamura, Yusuke
Zondervan, Krina T.
Zembutsu, Hitoshi
Montgomery, Grant W.
[J]. NATURE GENETICS, 2012, 44 (12) : 1355 - 1359
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Dale R Nyholt
Siew-Kee Low
Carl A Anderson
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Anjali K Henders
Nicholas G Martin
John Attia
Elizabeth G Holliday
Mark McEvoy
Rodney J Scott
Stephen H Kennedy
Susan A Treloar
Stacey A Missmer
Sosuke Adachi
Kenichi Tanaka
Yusuke Nakamura
Krina T Zondervan
Hitoshi Zembutsu
Grant W Montgomery
[J]. Nature Genetics, 2012, 44 : 1355 - 1359
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van der Most, Peter
Wang, Siqi
Guan, Weihua
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Heinzel, Andreas
Israni, Ajay
Jacobson, Pamala
Keating, Brendan
Conlon, Peter
Oberbauer, Rainer
Snieder, Harold
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Cho, Michael H.
McDonald, Merry-Lynn N.
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Mattheisen, Manuel
Castaldi, Peter J.
Hersh, Craig P.
DeMeo, Dawn L.
Sylvia, Jody S.
Ziniti, John
Laird, Nan M.
Lange, Christoph
Litonjua, Augusto A.
Sparrow, David
Casaburi, Richard
Barr, R. Graham
Regan, Elizabeth A.
Make, Barry J.
Hokanson, John E.
Lutz, Sharon
Dudenkov, Tanda Murray
Farzadegan, Homayoon
Hetmanski, Jacqueline B.
Tal-Singer, Ruth
Lomas, David A.
Bakke, Per
Gulsvik, Amund
Crapo, James D.
Silverman, Edwin K.
Beaty, Terri H.
[J]. LANCET RESPIRATORY MEDICINE, 2014, 2 (03): : 214 - 225
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Paternoster, L.
Standl, M.
Baurecht, H.
Ramasamy, A.
Bnnelykke, K.
Duijts, L.
Jarvelin, M.
Ferreira, M.
Wichmann, H. E.
Strachan, D.
Thyssen, J.
Nohr, E.
Jarvis, D.
Feenstra, B.
Sleiman, P.
Glass, D.
Palmer, L.
Probst-Hensch, N.
Jacobsson, B.
Curtin, J.
Boomsma, D.
Koppelmann, G.
Saaf, A.
Bisgaard, H.
Heinrich, J.
Evans, D.
Weidinger, S.
[J]. EXPERIMENTAL DERMATOLOGY, 2012, 21 (03) : e3 - e3

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