Multicenter Study

. 2024 Nov;39(11):2110-2116.

doi: 10.1002/mds.29968. Epub 2024 Sep 17.

Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

Björn-Hergen Laabs¹, Katja Lohmann², Eva-Juliane Vollstedt², Tobias Reinberger³, Lisa-Marie Nuxoll¹, Gamze Kilic-Berkmen⁴, Joel S Perlmutter⁵, Sebastian Loens⁶, Carlos Cruchaga⁷, Andre Franke⁸, Valerija Dobricic⁹, Frauke Hinrichs², Anne Grözinger², Eckart Altenmüller¹⁰, Steven Bellows¹¹, Sylvia Boesch¹², Susan B Bressman^{13

14}, Kevin R Duque¹⁵, Alberto J Espay¹⁵, Andreas Ferbert¹⁶, Jeanne S Feuerstein¹⁷, Samuel Frank¹⁸, Thomas Gasser^{19

20}, Bernhard Haslinger²¹, Robert Jech²², Frank Kaiser^{23

24}, Christoph Kamm²⁵, Katja Kollewe²⁶, Andrea A Kühn²⁷, Mark S LeDoux^{28

29}, Ebba Lohmann^{19

20}, Abhimanyu Mahajan³⁰, Alexander Münchau⁶, Trisha Multhaupt-Buell³¹, Alexander Pantelyat³², Sarah E Pirio Richardson³³, Deborah Raymond¹³, Stephen G Reich³⁴, Rachel Saunders Pullman^{13

14}, Barbara Schormair^{35

36}, Nutan Sharma³¹, Azadeh Hamzehei Sichani^{14

37}, Kristina Simonyan^{14

30

31

37}, Jens Volkmann³⁸, Aparna Wagle Shukla³⁹, Juliane Winkelmann^{35

36

40}, Laura J Wright⁴¹, Michael Zech^{35

36}, Kirsten E Zeuner⁴², Simone Zittel⁴³, Meike Kasten^{2

44}, Yan V Sun⁴⁵, Tobias Bäumer⁶, Norbert Brüggemann⁴⁶, Laurie J Ozelius³¹, Hyder A Jinnah⁴, Christine Klein², Inke R König¹

Affiliations

¹ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
² Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
³ Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
⁴ Department of Neurology, Emory University, Atlanta, Georgia, USA.
⁵ Department of Neurology, Radiology and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
⁶ Institute of Systems Motor Science, CBBM, University of Lübeck, Lübeck, Germany.
⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
⁹ Lübeck Interdisciplinary Platform for Genome Analysis, University of Lübeck, Lübeck, Germany.
¹⁰ Institute of Music Physiology and Musician's Medicine, Hanover University of Music, Drama and Media, Hanover, Germany.
¹¹ Parkinson's Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, Texas, USA.
¹² Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York, USA.
¹⁴ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁶ Department of Neurology, Kassel School of Medicine, Klinikum Kassel, Kassel, Germany.
¹⁷ Department of Neurology, School of Medicine, University of Colorado, Aurora, Colorado, USA.
¹⁸ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Department of Neurology, University of Tübingen, Tübingen, Germany.
²⁰ Hertie Institute for Clinical Brain Research and DZNE, University of Tübingen, Tübingen, Germany.
²¹ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
²² Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
²³ Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁴ Essener Zentrum für Seltene Erkrankungen, University Hospital Essen, Essen, Germany.
²⁵ Department of Neurology, University Medical Centre Rostock, Rostock, Germany.
²⁶ Clinic for Neurology, Hannover Medical School, Hannover, Germany.
²⁷ Department of Neurology and Experimental Neurology, Charité-University Medicine, Berlin, Germany.
²⁸ Veracity Neuroscience LLC, Memphis, Tennessee, USA.
²⁹ Department of Psychology, University of Memphis, Memphis, Tennessee, USA.
³⁰ Department of Neurological Sciences, RUSH University, Chicago, Illinois, USA.
³¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³² Department of Neurology, Johns Hopkins Medicine, Baltimore, Maryland, USA.
³³ Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
³⁴ University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁵ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
³⁶ Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany.
³⁷ Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.
³⁸ Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
³⁹ Department of Neurology, University of Florida, Gainesville, Florida, USA.
⁴⁰ Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
⁴¹ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴² Clinic for Neurology, Christian-Albrechts-University, Kiel, Germany.
⁴³ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
⁴⁵ Department of Epidemiology, Emory University Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁴⁶ Department of Neurology, University of Lübeck, Lübeck, Germany.

PMID: 39287592
PMCID: PMC11975433 (available on 2025-11-01)
DOI: 10.1002/mds.29968

Multicenter Study

Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

Björn-Hergen Laabs et al. Mov Disord. 2024 Nov.

. 2024 Nov;39(11):2110-2116.

doi: 10.1002/mds.29968. Epub 2024 Sep 17.

Authors

Affiliations

¹ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.
² Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
³ Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
⁴ Department of Neurology, Emory University, Atlanta, Georgia, USA.
⁵ Department of Neurology, Radiology and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
⁶ Institute of Systems Motor Science, CBBM, University of Lübeck, Lübeck, Germany.
⁷ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
⁹ Lübeck Interdisciplinary Platform for Genome Analysis, University of Lübeck, Lübeck, Germany.
¹⁰ Institute of Music Physiology and Musician's Medicine, Hanover University of Music, Drama and Media, Hanover, Germany.
¹¹ Parkinson's Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, Texas, USA.
¹² Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹³ Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, New York, USA.
¹⁴ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁶ Department of Neurology, Kassel School of Medicine, Klinikum Kassel, Kassel, Germany.
¹⁷ Department of Neurology, School of Medicine, University of Colorado, Aurora, Colorado, USA.
¹⁸ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁹ Department of Neurology, University of Tübingen, Tübingen, Germany.
²⁰ Hertie Institute for Clinical Brain Research and DZNE, University of Tübingen, Tübingen, Germany.
²¹ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
²² Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
²³ Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁴ Essener Zentrum für Seltene Erkrankungen, University Hospital Essen, Essen, Germany.
²⁵ Department of Neurology, University Medical Centre Rostock, Rostock, Germany.
²⁶ Clinic for Neurology, Hannover Medical School, Hannover, Germany.
²⁷ Department of Neurology and Experimental Neurology, Charité-University Medicine, Berlin, Germany.
²⁸ Veracity Neuroscience LLC, Memphis, Tennessee, USA.
²⁹ Department of Psychology, University of Memphis, Memphis, Tennessee, USA.
³⁰ Department of Neurological Sciences, RUSH University, Chicago, Illinois, USA.
³¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³² Department of Neurology, Johns Hopkins Medicine, Baltimore, Maryland, USA.
³³ Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
³⁴ University of Maryland School of Medicine, Baltimore, Maryland, USA.
³⁵ Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
³⁶ Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany.
³⁷ Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.
³⁸ Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
³⁹ Department of Neurology, University of Florida, Gainesville, Florida, USA.
⁴⁰ Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
⁴¹ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴² Clinic for Neurology, Christian-Albrechts-University, Kiel, Germany.
⁴³ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁴ Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
⁴⁵ Department of Epidemiology, Emory University Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁴⁶ Department of Neurology, University of Lübeck, Lübeck, Germany.

PMID: 39287592
PMCID: PMC11975433 (available on 2025-11-01)
DOI: 10.1002/mds.29968

Abstract

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.

Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.

Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.

Results: This GWAS identified no common genome-wide significant loci that could be replicated despite sufficient power to detect meaningful effects. Power analyses imply that the effects of individual variants are likely very small.

Conclusions: Moderate single-nucleotide polymorphism-based heritability indicates that common variants do not contribute to isolated dystonia in this cohort. Sequence-based GWASs (eg, by whole-genome sequencing) might help to better understand the genetic basis. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: GWAS; age at onset; case–control; clinical score; isolated dystonia.

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Conflict of interest statement

Relevant conflicts of interest/financial disclosures: C.C. has received research support from GSK, EISAI, Danaher, Biogen, Alector, and Centene; receives research support from the National Institutes of Health (NIH), Chan Zuckerberg Initiative, The Michael J. Fox Foundation, Cure Alzheimer’s Fund, Alzheimer’s Association Zenith Fellows Award, and an anonymous foundation; is a member of the advisory board of GSK, AbbVie, Circular Genomics, and ADMit; and owns Circular Genomics stock. K.R.D. has received honoraria from the Parkinson’s Foundation for translation support. A.J.E. has received grant support from the NIH and The Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly USWorldMeds), NeuroDiagnostics, Inc. (SYNAPS Dx), and Herantis Pharma; has received publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; cofounded REGAIN Therapeutics; and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” C. Kamm has received honoraria as a consultant for Ipsen, Roche, and Biogen, outside of the submitted work. M.S.L. has been a consultant for Supernus and Solstice; has been a speaker for Teva Pharmaceutical Industries, Neurocrine, Amneal, USWorldMeds, Supernus, Kyowa Kirin, Otsuka America Pharmaceutical, and Lundbeck; receives publishing royalties from Elsevier (Animal Models of Movement Disorders, and Movement Disorders: Genetics and Models) and TheBookPatch (Parkinson’s Disease Poetry); and his research has been funded by the NIH, Axovant Sciences, Wave Life Sciences, Teva Pharmaceutical Industries, Pharma Two B, Revance, Cerevel, Annovis, Aeon, NeuroDerm, Sage Therapeutics, Inhibikinase Therapeutics, UCB Pharma, Intra-Cellular Therapies, Dystonia Medical Research Foundation, and Benign Essential Tremor Research Foundation. A. Mahajan has been funded by the Dystonia Medical Research Foundation, Sunflower Parkinson’s Disease Foundation, and the Parkinson’s Foundation, outside of the submitted work. A.P. reports grant support from the NIH as principal investigator (PI)/co-PI; serves on the Scientific Advisory Board of Medrhythms, Inc.; is on the board of CurePSP; and has received royalties from Springer. S.G.R. has received speakers’ honoraria from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology; book royalties from Oxford, Springer, and Informa; and consulting fees from Best Doctors and UpToDate. S.E.P.R. has received honoraria for lectures from the International Parkinson’s Disease and Movement Disorders Society and the American Academy of Neurology; serves on the Scientific Advisory Boards for private foundations including the Benign Essential Blepharospasm Research Foundation and the Dystonia Medical Research Foundation; and has received royalties from Springer. K.S. receives funding from the NIH and the Department of Defense; serves on the Scientific Advisory Board of the Tourette Association of America and the Voice Foundation; and received consulting fees from Jazz Pharmaceuticals Inc. and AbbVie Inc. A.W.S. reports grant support from the NIH; has received funding from Benign Essential Blepharospasm Research foundation, Dystonia Coalition, Dystonia Medical Research foundation, and National Organization for Rare Disorders; has received consultant fees from Merz, Jazz, and Acadia; and is the current Vice President for the Tremor Research Group and recent advisor for Supernus and Biogen-Sage. N.B. has received honoraria and support for participation in advisory boards from Abbott, AbbVie, Biogen, Biomarin, Bridgebio, Centogene, Esteve, Ipsen, Merz, and Zambon. H.A.J. has active or recent grant support (recent, active, or pending) from the US government (NIH), private philanthropic organizations (Cure Dystonia Now, Lesch–Nyhan Syndrome Children’s Research Foundation), and industry (AbbVie, Addex, Aeon, Sage, Jazz); has served on advisory boards or as a consultant for AbbVie, Addex, Allergan, Ipsen, Merz, and Revance; has received stipends for administrative work from the International Parkinson’s Disease and Movement Disorders Society; has served on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, the Dystonia Medical Research Foundation, and the Tourette Association of America; and is PI for the Dystonia Coalition, which has received the majority of its support through the NIH. C. Klein serves as a medical advisor to Centogene and Retromer Therapeutics and received speakers’ honoraria from Bial and Desitin. The remaining authors declare no conflicts of interest.

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Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

Affiliations

Genetic Risk Factors in Isolated Dystonia Escape Genome-Wide Association Studies

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Conflict of interest statement

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