Genome-wide association study in essential tremor identifies three new loci PMID: 27797806

Target-related Cytokines

2026-09-23

Genome-wide association study in essential tremor identifies three new loci

Brain. 2016 Dec;139(Pt 12):3163-3169. doi: 10.1093/brain/aww242.

Stefanie H Müller ¹ , Simon L Girard ² ³ , Franziska Hopfner ¹ , Nancy D Merner ³ ⁴ , Cynthia V Bourassa ³ , Delia Lorenz ⁵ , Lorraine N Clark ⁶ , Lukas Tittmann ⁷ , Alexandra I Soto-Ortolaza ⁸ , Stephan Klebe ⁹ ¹⁰ , Mark Hallett ¹¹ , Susanne A Schneider ¹ ¹² , Colin A Hodgkinson ¹³ , Wolfgang Lieb ⁷ , Zbigniew K Wszolek ⁸ , Manuela Pendziwiat ¹⁴ , Oswaldo Lorenzo-Betancor ¹⁵ ¹⁶ , Werner Poewe ¹⁷ , Sara Ortega-Cubero ¹⁵ ¹⁶ , Klaus Seppi ¹⁷ , Alex Rajput ¹⁸ , Anna Hussl ¹⁷ , Ali H Rajput ¹⁸ , Daniela Berg ¹ , Patrick A Dion ³ , Isabel Wurster ¹⁹ , Joshua M Shulman ²⁰ ²¹ , Karin Srulijes ¹⁹ , Dietrich Haubenberger ¹¹ , Pau Pastor ¹⁵ ¹⁶ , Carles Vilariño-Güell ²² , Ronald B Postuma ³ ²³ , Geneviève Bernard ³ ²⁴ , Karl-Heinz Ladwig ²⁵ ²⁶ , Nicolas Dupré ²⁷ , Joseph Jankovic ²⁰ , Konstantin Strauch ²⁸ ²⁹ , Michel Panisset ³⁰ , Juliane Winkelmann ³¹ ³² , Claudia M Testa ³³ , Eva Reischl ²⁵ ³⁴ , Kirsten E Zeuner ¹ , Owen A Ross ⁸ , Thomas Arzberger ³⁵ ³⁶ , Sylvain Chouinard ³⁰ , Günther Deuschl ¹ , Elan D Louis ³⁷ , Gregor Kuhlenbäumer ¹ , Guy A Rouleau ³⁸

Affiliations

1. 1 Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
2. 2 Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Saguenay, Canada.
3. 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.
4. 4 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
5. 5 University Children's Hospital, University of Würzburg, Würzburg, Germany.
6. 6 Department of Pathology and Cell Biology, Taub Institute, Columbia University, New York City, NY, USA.
7. 7 Institute of Epidemiology, Christian-Albrechts University Kiel and Biobank POPGEN, Kiel, Germany.
8. 8 Department of Neuroscience and Neurology, Mayo Clinic, Florida, USA.
9. 9 Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
10. 10 Department of Neurology, University Hospital Freiburg, Freiburg im Breisgau, Germany.
11. 11 NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
12. 12 Department of Neurology, Ludwig-Maximilians-Universität München, Munich Germany.
13. 13 NIAAA/NIH Bethesda MD, USA.
14. 14 Department of Paediatric Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Germany.
15. 15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
16. 16 Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona, Barcelona, Spain.
17. 17 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
18. 18 University of Saskatchewan and Saskatoon Health Region, Saskatoon, SK, Canada.
19. 19 Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases, Tübingen, Germany.
20. 20 Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
21. 21 Departments of Molecular and Human Genetics and Neuroscience, and Program in Developmental Biology, Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
22. 22 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
23. 23 Department of Neurology, Montreal General Hospital, Montréal, QC, Canada.
24. 24 Departments of Pediatrics, Neurology and Neurosurgery, division of Pediatric Neurology, Montreal Children's Hospital, Montreal, Canada.
25. 25 Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
26. 26 Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar, Technische Universität, Munich, Germany.
27. 27 Faculté de Médecine, Université Laval, CHU de Québec (Enfant-Jésus), Québec, QC, Canada.
28. 28 Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
29. 29 Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
30. 30 Unité des troubles du mouvement André Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
31. 31 Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
32. 32 Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, and Munich Cluster for Systems Neurology (Synergy), Munich, Germany.
33. 33 Department of Neurology and Parkinson's and Movement Disorders Center, Virginia Commonwealth University, Richmond VA, USA.
34. 34 Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
35. 35 Center for Neuropathology and Prion Research, University of Munich, 80539 München, Germany.
36. 36 Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
37. 37 Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.
38. 3 Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montréal, Canada [email protected].

Abstract

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

Keywords

essential tremor; genetics; genome-wide association study; movement disorders; tremor.