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

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 >...

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Published in	Movement disorders Vol. 39; no. 11; pp. 2110 - 2116
Main Authors	Laabs, Björn‐Hergen, Lohmann, Katja, Vollstedt, Eva‐Juliane, Reinberger, Tobias, Nuxoll, Lisa‐Marie, Kilic‐Berkmen, Gamze, Perlmutter, Joel S., Loens, Sebastian, Cruchaga, Carlos, Franke, Andre, Dobricic, Valerija, Hinrichs, Frauke, Grözinger, Anne, Altenmüller, Eckart, Bellows, Steven, Boesch, Sylvia, Bressman, Susan B., Duque, Kevin R., Espay, Alberto J., Ferbert, Andreas, Feuerstein, Jeanne S., Frank, Samuel, Gasser, Thomas, Haslinger, Bernhard, Jech, Robert, Kaiser, Frank, Kamm, Christoph, Kollewe, Katja, Kühn, Andrea A., LeDoux, Mark S., Lohmann, Ebba, Mahajan, Abhimanyu, Münchau, Alexander, Multhaupt‐Buell, Trisha, Pantelyat, Alexander, Pirio Richardson, Sarah E., Raymond, Deborah, Reich, Stephen G., Saunders Pullman, Rachel, Schormair, Barbara, Sharma, Nutan, Sichani, Azadeh Hamzehei, Simonyan, Kristina, Volkmann, Jens, Wagle Shukla, Aparna, Winkelmann, Juliane, Wright, Laura J., Zech, Michael, Zeuner, Kirsten E., Zittel, Simone, Kasten, Meike, Sun, Yan V., Bäumer, Tobias, Brüggemann, Norbert, Ozelius, Laurie J., Jinnah, Hyder A., Klein, Christine, König, Inke R.
Format	Journal Article
Language	English
Published	Hoboken, USA John Wiley & Sons, Inc 01.11.2024 Wiley Subscription Services, Inc
Subjects	Adult age at onset case–control clinical score Dystonia Dystonia - genetics Dystonic Disorders - genetics Female Genetic Predisposition to Disease - genetics Genome-Wide Association Study Genomes GWAS Heritability Humans isolated dystonia Male Middle Aged Movement disorders Nucleotide sequence Polymorphism, Single Nucleotide - genetics Risk Factors Somatic chromosomes Whole genome sequencing clinical score GWAS case–control isolated dystonia age at onset
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ISSN	0885-3185 1531-8257 1531-8257
DOI	10.1002/mds.29968

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Summary:	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.
Bibliography:	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. Björn‐Hergen Laabs, Katja Lohmann, and Eva‐Juliane Vollstedt contributed equally to this work. Christine Klein and Inke R. König are cosenior authors and contributed equally to this work. Relevant conflicts of interest/financial disclosures Funding agencies This study was supported by the Deutsche Forschungsgemeinschaft (FOR2488 to C. Klein, N.B., K.L., and I.R.K.; EXC2167 to A.Franke), the National Institutes of Health (NS095445, NS116025, NS065701, and TR001456 to the Dystonia Coalition; P01NS087997 to L.J.O. and N.S.; R01DC011805, R01DC012545, and R01NS088160 to K.S.; and R01NS026656 to S.B.B.), the Federal Ministry of Education and Research in Germany (BMBF; 01GM1514A to the DysTract consortium and 01GM2302 to M.Z.), National Institute for Neurological Research, Czech Republic, European Union, Charles University (LX22NPO5107 to R.J.), European Joint Programme on Rare Diseases (EJP RD Joint Transnational Call 2022 to M.Z.), Free State of Bavaria, and Technical University of Munich (to M.Z.). ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0885-3185 1531-8257 1531-8257
DOI:	10.1002/mds.29968