Yan V Sun1,2, Chengchen Li1, Qin Hui1, Yunfeng Huang1, Richard Barbano3, Ramon Rodriguez4, Irene A Malaty5, Stephen Reich6, Kimberly Bambarger6, Katie Holmes6, Joseph Jankovic7, Neepa J Patel8, Emmanuel Roze9, Marie Vidailhet9, Brian D Berman10, Mark S LeDoux11, Alberto J Espay12, Pinky Agarwal13, Sarah Pirio-Richardson14, Samuel A Frank15, William G Ondo16, Rachel Saunders-Pullman17, Sylvain Chouinard18, Stover Natividad19, Alfredo Berardelli20, Alexander Y Pantelyat21, Allison Brashear22, Susan H Fox23, Meike Kasten24,25, Ulrike M Krämer26, Miriam Neis26,27, Tobias Bäumer24,28, Sebastian Loens24,28, Max Borsche24,26, Simone Zittel29, Antonia Maurer29, Mathias Gelderblom29, Jens Volkmann30, Thorsten Odorfer30, Andrea A Kühn31, Friederike Borngräber31, Inke R König32, Carlos Cruchaga33, Adam C Cotton34, Gamze Kilic-Berkmen34, Alan Freeman34, Stewart A Factor34, Laura Scorr34, J Douglas Bremner35,36, Viola Vaccarino1, Arshed A Quyyumi37, Christine Klein24, Joel S Perlmutter38, Katja Lohmann24, Hyder A Jinnah34,39. 1. Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA. 2. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, USA. 3. Movement Disorders Division, University of Rochester, Rochester, New York, USA. 4. Neurology One, Orlando, Florida, USA. 5. Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA. 6. Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. 7. Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. 8. Department of Neurology, Henry Ford Health System, Henry Ford Hospital, Detroit, Michigan, USA. 9. Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle; Assistance Publique - Hôpitaux de Paris, Hôpital Salpêtrière, Département de Neurologie, Paris, France. 10. Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, USA. 11. Department of Psychology, University of Memphis, Memphis, Tennessee, USA. 12. James J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA. 13. Booth Gardner Parkinson's Care Center, Evergreen Health, Kirkland, Washington, USA. 14. Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA. 15. Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 16. Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, Texas, USA. 17. Icahn School of Medicine at Mount Sinai, Movement Disorders, Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA. 18. Unité des troubles du mouvement André-Barbeau, Centre Hospitalier de l'Université de Montréal, Montreal, Canada. 19. Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. 20. Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed, Rome, Italy. 21. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 22. Neurology, University of California, Davis, Sacramento, California, USA. 23. University of Toronto, Edmond J Safra Program in Parkinson Disease; Movement Disorder Clinic, Toronto Western Hospital, Toronto, Ontario, Canada. 24. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. 25. Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. 26. Department of Neurology, University of Lübeck, Lübeck, Germany. 27. Institute for Health Sciences, Department of Midwifery Science, University of Lübeck, Lübeck, Germany. 28. Institute of Systemic Motor Research, University of Lübeck, Lübeck, Germany. 29. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 30. Department of Neurology, University Hospital Würzburg, Würzburg, Germany. 31. Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany. 32. Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany. 33. Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA. 34. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. 35. Atlanta VA Medical Center, Decatur, Georgia, USA. 36. Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, Georgia, USA. 37. Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. 38. Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, Missouri, USA. 39. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
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.
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.
Authors: Alberto Albanese; Kailash Bhatia; Susan B Bressman; Mahlon R Delong; Stanley Fahn; Victor S C Fung; Mark Hallett; Joseph Jankovic; Hyder A Jinnah; Christine Klein; Anthony E Lang; Jonathan W Mink; Jan K Teller Journal: Mov Disord Date: 2013-05-06 Impact factor: 10.338
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Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: Karin Tuschl; Esther Meyer; Leonardo E Valdivia; Ningning Zhao; Chris Dadswell; Alaa Abdul-Sada; Christina Y Hung; Michael A Simpson; W K Chong; Thomas S Jacques; Randy L Woltjer; Simon Eaton; Allison Gregory; Lynn Sanford; Eleanna Kara; Henry Houlden; Stephan M Cuno; Holger Prokisch; Lorella Valletta; Valeria Tiranti; Rasha Younis; Eamonn R Maher; John Spencer; Ania Straatman-Iwanowska; Paul Gissen; Laila A M Selim; Guillem Pintos-Morell; Wifredo Coroleu-Lletget; Shekeeb S Mohammad; Sangeetha Yoganathan; Russell C Dale; Maya Thomas; Jason Rihel; Olaf A Bodamer; Caroline A Enns; Susan J Hayflick; Peter T Clayton; Philippa B Mills; Manju A Kurian; Stephen W Wilson Journal: Nat Commun Date: 2016-05-27 Impact factor: 14.919