Abstract
Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10−8). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10−6). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10−8, minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia.
| Original language | English |
|---|---|
| Journal | Movement Disorders |
| Volume | 36 |
| Issue number | 12 |
| Pages (from-to) | 2795-2801 |
| Number of pages | 7 |
| ISSN | 0885-3185 |
| DOIs | |
| Publication status | Published - 12.2021 |
Funding
B.D.B. has received research grant support from the Parkinson's Foundation, Dana Foundation, NIH (NIH/NCATS Colorado CTSI Grant Number KL2 TR001080), Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), and from Mary Rossick Kern and Jerome H. Kern. He also serves on the medical advisory boards for the Benign Essential Blepharospasm Research Foundation and the National Spasmodic Torticollis Association. : Y.V.S., C.L., Q.H., and H.A.J. are partially supported by the National Institute of Health grant NS096455 and the Dystonia Medical Research Foundation. This work was also supported in part by grants to the Dystonia Coalition, a part of the Rare Diseases Clinical Research Network of the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences (Grant numbers NS065701, TR001456, and NS116025). K.L., I.R.K., and C.K. are supported by the DFG (FOR2488). The DysTract study has been supported by the Federal Ministry of Education and Sciences (BMBF) in Germany (01GM1514B, to K.L. and C.K.). U.K., M.K., and C.K. were supported by the DFG (TR‐SFB134). Funding agencies S.Z. has received grant support from the European Union and Werner Otto Foundation and honoraria from Merz Pharmaceuticals and Brainlab AG. E.R. received research support from Merz‐Pharma, Orkyn, Aguettant, Elivie, Ipsen, Fondation Desmarest, AMADYS, Agence Nationale de la Recherche, and Fonds de Dotation Brou de Laurière; has served on scientific advisory boards for Orkyn, Aguettant, Merz‐Pharma and has received speech honoraria from Orkyn, Aguettant, Merz‐Pharma, Medday‐Pharma, Everpharma, International Parkinson and Movement disorders Society; received travel grant from Vitalair, Aguettant, Merz‐Pharma, Ipsen, Merck, Orkyn, Elivie, Dystonia medical Research Foundation, International Parkinson and Movement disorders Society, European Academy of Neurology, International Association of Parkinsonism and Related Disorders. S.H.F. has received Clinic support from the Edmond J Safra Foundation for Parkinson Research; National Parkinson Foundation and the Toronto Western and General Foundation. Salary from UHN Dept of Medicine Practice Plan. Research funding from Michael J Fox Foundation for Parkinson Research, NIH (Dystonia Coalition); CIHR; Parkinson Canada. Honoraria from the International Parkinson and Movement Disorder Society and American Academy of Neurology. Site PI for Clinical Trials for Biotie, Cynapsus, Eisai, Revance. Consultancy/speaker fees from Acadia, Atuka, Sunovion, Teva, Paladin; royalties from Oxford University Press. I.R.K. has received grant support from the German Research Foundation, BMBF, German Cancer Aid. P.A. has received honoraria from Sunovion, Acadia, Amneal, Accorda, ADAMA, Kyowa Kirin, and Supernus for speaking. She has also received consulting fees from ADAMAS CALA Health, and Sunovion. Research support has been received from US WorldMeds, Centogene, Biogen, Merck, Sun Pharma, Advanced Research Company Limited (SPARC) Anexxon Inc, CHDI Foundation, Roche. T.B. has received grant support from DFG FOR 2698. He has also received honoraria or consulting fees from Ipsen Pharma, Allergan, Merz Pharmaceuticals. B.D.B. has received research grant support from the Parkinson's Foundation, Dana Foundation, NIH (NIH/NCATS Colorado CTSI Grant Number KL2 TR001080), Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), and from Mary Rossick Kern and Jerome H. Kern. He also serves on the medical advisory boards for the Benign Essential Blepharospasm Research Foundation and the National Spasmodic Torticollis Association. F.B. has received grant support from Clinician Scientist Program, BIH, Charit?-Universit?tsmedizin Berlin, and Max-Delbr?ck Centre. M.B. has received honoraria from Ipsen Pharma. A.B. has active or recent grant support from the NIH Revance, Allergan, Merz, Ipsen. She has served as a consultant or on advisory boards for Revance, Ipsen, Allergan, and Merz. She is a board member for the American Board of Psychiatry and Neurology, California Institute of Regenerative Medicine, McKnight Brain Research Foundation, Latinx Physicians of California. She is founder and board member of Care Directions. C.C. has received research support from Biogen, EISAI, and Alector. A.J.E. has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; honoraria from Acadia, Sunovion, USWorldMeds; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. C.K. has received grant support from the Hermann and Lilly Schilling Foundation; the German Research Foundation; the BMBF; the German Research Foundation; the European Community; intramural funds from the University of Luebeck. She has served as medical advisor to Centogene. She has also received honoraria from the Else Kroener Fresenius Foundation. F.B. has received grant support from Clinician Scientist Program, BIH, Charité‐Universitätsmedizin Berlin, and Max‐Delbrück Centre. K.L. has received grant support from German Research Foundation; Federal Ministry of Education and Science (BMBF); Movement Disorder Society; Damp‐Stiftung. S.A.F. has honoraria from Lundbeck, Teva, Sunovion, Biogen, Acadia, Neuroderm, Acorda, CereSpir; grants from Ipsen, Medtronics, Boston Scientific, Teva, US World Meds, Sunovion Therapeutics, Vaccinex, Voyager, Jazz Pharmaceuticals, Lilly, CHDI Foundation, Michael J. Fox Foundation, NIH; Royalties from Demos, Blackwell Futura, Springer for textbooks, Uptodate; and other support from Bracket Global LLC, CNS Ratings LLC. M.K. has received grant support from TCRC‐134, FOR 2488. W.G.O., MD has received honorarium for speaking bureau from Teva, ACADIA, Acorda, Neurocrine, UCBPharma, USWorldMeds, and Lundbeck. He has received research grants from Biogen, Lundbeck, Sun, Restless Legs Syndrome Foundation, Parkinson's Study Group, Lilly, and Revance. He receives royalties from the books , , and . Restless Legs Syndrome Movement Disorders in Clinical Practice UpToDate J.V. has received grant support from Boston Scientific, Medtronic, BMBF, Deutsche Forschungsgemeinschaft. He has received honoraria from Boston Scientific, Medtronic, BMBF, Deutsche Forschungsgemeinschaft. He has served as a consultant or on an advisory board for Boston Scientific, Newronika, and Medtronic. M.S.L. serves on the speaker's bureaus for Acadia, Teva, Acorda and Adamas, and editorial boards of and ; has received research support from the National Institutes of Health, Dystonia Medical Research Foundation, Department of Defense, Michael J. Fox Foundation, Revance, and PharmaTwoB; and receives royalty payments from Elsevier for editing and . Neurology Tremor and Other Hyperkinetic Movements Animal Models of Movement Disorders Movement Disorders: Genetics and Models U.M.K. has received grant support from the German Research Foundation. M.G. has received grant support from Merz Pharmaceuticals, Allergan, DFG, Werner Otto Stiftung, Ostseeförderung. He has served on advisory boards for Merz Pharmaceuticals and Allergan, and has received honoraria from Merz Pharmaceuticals, Allergan, and Ipsen. T.B. has received grant support from DFG FOR 2698. He has also received honoraria or consulting fees from Ipsen Pharma, Allergan, Merz Pharmaceuticals. H.A.J. has active or recent grant support from the US government (National Institutes of Health), private philanthropic organizations (Cure Dystonia Now), and industry (Cavion Therapeutics, Retrophin Inc., Revance Therapeutics). He has also served on advisory boards or as a consultant for Abide Therapeutics, Allergan Inc., CoA Therapeutics, Retrophin Inc, and Revance Therapeutics. He has received honoraria or stipends for lectures or administrative work from the International Parkinson's Disease and Movement Disorders Society. He serves on the scientific advisory boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, the Dystonia Medical Research Foundation, the Tourette Association of American, and Tyler's Hope for a Cure. He also is director of the Dystonia Coalition, which receives the majority of its support through NIH grants (NS116015, NS067501, and TR001456 from the National Institutes of Neurological Disorders and Stroke and the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). The Dystonia Coalition has received additional material or administrative support from industry sponsors (Allergan Inc. and Merz Pharmaceuticals) as well as private foundations (the American Dystonia Society, Beat Dystonia, the Benign Essential Blepharospasm Foundation, Cure Dystonia Now, Dystonia Europe, Dystonia Inc., Dystonia Ireland, the Dystonia Medical Research Foundation, the Foundation for Dystonia Research, the National Spasmodic Dysphonia Association, and the National Spasmodic Torticollis Association).
Research Areas and Centers
- Research Area: Medical Genetics
DFG Research Classification Scheme
- 2.23-02 Molecular Biology and Physiology of Nerve and Glial Cells
